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TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE,
OBSERVER-BLINDED, RANDOMIZED CONTROLLED TRIAL (TRACE)
by
Adriana Micheline Workewych
A thesis submitted in conformity with the requirements for the degree of Master of Science
Institute of Medical Science
University of Toronto
© Copyright by Adriana Micheline Workewych 2018
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TRANEXAMIC ACID IN THE TREATMENT OF RESIDUAL CHRONIC SUBDURAL HEMATOMA: A SINGLE-CENTRE,
OBSERVER-BLINDED, RANDOMIZED CONTROLLED TRIAL (TRACE)
Adriana Micheline Workewych
Master of Science
Institute of Medical Science University of Toronto
2018
ABSTRACT
Chronic subdural hematoma (CSDH) is a frequent consequence of head trauma, particularly
in older individuals. Given the aging of populations globally, its incidence is projected to
increase substantially. Hyperfibrinolysis may be central to CSDH enlargement by causing
excessive clot degradation and liquefaction, impeding resorption. The only current standard
treatment for CSDH is surgery, however, up to 31% of residual hematomas enlarge,
requiring reoperation. Tranexamic acid (TXA), an antifibrinolytic medication that prevents
excessively rapid clot breakdown, may help prevent CSDH enlargement, potentially
eliminating the need for repeat surgery. To evaluate the feasibility of conducting a trial
investigating TXA efficacy in residual CSDH, we conducted an observer-blinded, pilot
randomized controlled trial (RCT). We showed this trial was feasible and safe, reporting only
minor to moderate AEs, and an attrition rate of 4%. The results from this study will inform
the conduct of a double-blinded RCT investigating TXA efficacy in post-operative CSDH
management.
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ACKNOWLEDGEMENTS
First, I would like to thank my supervisor Dr. Michael Cusimano, my mentor for nearly six
years. You have always given me more opportunity than I could have ever hoped for – I
could not ask for a more dedicated teacher. Learning from you has been an absolute
privilege.
Thank you to my Program Advisory Committee members, Dr. Jeannie Callum and Dr. Olli
Saarela. It has been an honor to learn from you these past two years, and I am greatly
indebted to you for the time and effort you have put into guiding me through this trial and
thesis.
Thank you to Dr. Michael Meier, who enthusiastically contributed to the initial study idea.
Thank you to Dr. Irene Vanek – you have been the greatest support these past six years, and I
am grateful to learn from you every day.
Thank you to Dr. Walter Montanera for your guidance in reading CT imaging and your
expertise in designing the trials imaging protocol, and the substantial time and effort you put
into teaching me over the years.
Thank you to all the neurosurgeons at St. Michael’s Hospital – Dr. Julian Spears, Dr.
Jefferson Wilson, Dr. Sunit Das, Dr. Howard Ginsberg, and Dr. Richard Perrin – for
allowing your patients to be enrolled in the trial, and for your time in evaluating participant
eligibility.
Thank you to all the neurosurgery residents and fellows who took the time to screen and
speak to eligible patients: Dr. Farshad Nassiri, Dr. Benjamin Davidson, Dr. Arthur Dalton,
Dr, Allan Martin, Dr. Matthew Voisin, Dr. Justin Wang, and Dr. Ali Moghaddamjou.
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Thank you to all the registered nurses, pharmacists, and staff on the 9CC Neurosurgery
Ward, without whom conducting this trial would not have been possible: Tom Willis,
Theresa Cooke, Martine Andrews, Linda Lo, April Sienes, Jenny Pak, Elyse Kalpage, Renee
Ng, and Winnie Chan. Thank you to Judy Pararajasingham and Sanam Shinde for your help
organizing the study on the ward, and training staff in study procedures.
Thank you to all the members of the Research Pharmacy, namely Laura Parsons, Ann
Dowbenka and Gitana Ramonas, for your instrumental roles in randomizing our study
patients and dispensing the study drug so meticulously. Thank you to the pharmacists – Mae
Yuen, Emily Wong, Kevin Curley, and Mark Naccarato – who came in on evenings and
weekends to randomize patients and dispense the study drug.
Thank you to Cristina Lucarini, Lee-Ann Graham, Umberta Bottoni, Chris Northrup,
Shamim Sumar, Ann Augello, Barb Chamczuk, Brianna Richard-Gallant and Kacper
Michalak for helping me coordinate clinical study visits.
Thank you to all the members of the CT imaging department, including Shadi Mossaed and
Cristhian Moran, without whom we would not have been able to obtain our hematoma
volume measurements.
Thank you to Marlene Santos and Velma Marzinotto, who patiently guided me through the
many procedures of coordinating a clinical trial.
Thank you also for the academic and moral support of the members of the Injury Prevention
Research Office Team, both past and present: Stanley Zhang, Ling Chen, Karen Delina, Dr.
Zsolt Zador, Dr. Kenny Yu, Dr. Omar Pathmanaban, Dr. Cesar Hincapie, Dr. Rowan Xing
and Julia Casey.
This work was supported by the AFP Innovation Funds. Thank you also to the Institute of
Medical science for awarding me with the Institute of Medical Science Admissions Awards
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and Open Fellowship Award, which have supported me in my academic pursuits, and for
which I am sincerely grateful.
Finally, thank you to the participants of this study, who, in a moment of great personal
stress, selflessly dedicated their time to the pursuit of science, in a mission to improve the
care of future patients suffering this affliction.
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This work is dedicated to Natalie, my better half – I will never be able to thank you enough for everything you have done for me.
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CONTRIBUTIONS
PAC members: intellectual contributions to the study design, protocol, and thesis revisions.
Research pharmacy department: study randomization and study drug dispensation.
Registered nurses: in-patient study drug administration.
Shadi Mossaed: coordinating the CT imaging department.
Dr. Rowan Xing: exploratory power calculation.
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TABLE OF CONTENTS
ACKNOWLEDGEMENTS………………………………………………………………...iii
CONTRIBUTIONS………………………………………………………………………...vii
TABLE OF CONTENTS………………………………………………………………….viii
ABBREVIATIONS………………………………………………………………………...xiv
LIST OF TABLES…………………………………………………………………………xvi
LIST OF FIGURES……………………………………………………………………….xvii
LIST OF APPENDICES…………………………………………………………………xviii
1. INTRODUCTION AND LITERATURE REVIEW
1.1 CHRONIC SUBDURAL HEMATOMA: THE CLINICAL PICTURE AND
CURRENT STANDARD OF CARE………………………………………………1
1.1.1 WHAT IS A CHRONIC SUBDURAL HEMATOMA?...………………………1
1.1.2 RELEVANT NEUROANATOMY AND FORMATION OF A CHRONIC
SUBDURAL HEMATOMA…….………………………………………………1
1.1.3 ETIOLOGY, DEMOGRAPHICS AND CLINICAL PRESENTATION………3
1.1.4 RISK FACTORS FOR DEVELOPMENT………………………………………3
1.1.5 SUBDURAL HEMATOMA APPEARANCE ON AND SUBTYPE
CLASSIFICATION WITH DIAGNOSTIC IMAGING…………………………4
1.1.6 SURGICAL EVACUATION IS THE STANDARD TREATMENT FOR
CSDH…………………………………………………………………………….7
1.1.7 SURGICAL AND MEDICAL COMPLICATIONS AFTER SURGICAL
EVACUATION………………………………………………………………….8
1.2 THE CLINICAL PROBLEM: POST-OPERATIVE HEMATOMA
RECURRENCE…………………………………………………………………….9
1.2.1 DEMOGRAPHIC, CLINICAL, OPERATIVE, AND RADIOLOGIC
PREDICTORS OF POST-OPERATIVE CSDH RECURRENCE………………9
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1.2.2 RADIOLOGIC HEMATOMA SUBTYPES AS PREDICTORS OF
RECURRENCE………………………………………………………………...13
1.3 PATHOGENESIS AND THE MECHANISM OF CSDH ENLARGEMENT…14
1.3.1 OSMOLARITY………………………………………………………………....14
1.3.2 INFLAMMATION……………………………………………………………...14
1.3.3 ANGIOGENESIS…………………………………………………………….…17
1.3.4 HYPERFIBRINOLYSIS…………………………………………………….….18
1.3.5 MECHANICAL MECHANISMS………………………………………………22
1.4 NON-SURGICAL TREATMENT OF CSDH……………………………………22
1.5 TRANEXAMIC ACID…………………………………………………………….24
1.5.1 CURRENT THERAPEUTIC INDICATIONS…………………………………25
1.5.2 PHARMACOLOGY……………………………………………………………26
1.5.3 SAFETY………………………………………………………………………...27
1.5.4 CONTRAINDICATIONS……………………………………………………....27
1.5.5 WARNINGS AND PRECAUTIONS…………………………………………...28
1.5.6 DRUG INTERACTIONS……………………………………………………….30
1.5.7 SIDE EFFECTS AND ADVERSE EVENTS…………………………………..30
1.6 DOSING REGIMENS IN TRANEXAMIC ACID TREATMENT…………….30
1.7 TRANEXAMIC ACID TREATMENT IN TRAUMA AND NEUROSURGICAL
CONDITIONS………………………………………………………………….….31
2. STUDY RATIONALE AND DESIGN……………………………………………34
2.1 STUDY DESCRIPTION AND OBJECTIVES…………………………………...36
2.1.1 PRIMARY STUDY OBJECTIVE………………………………………………36
2.1.1.1 Feasibility………………………………………………………………………..36
2.1.2 SECONDARY STUDY OBJECTIVES…………………………………………36
2.1.2.1 Hematoma volume change………………………………………………………36
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2.1.2.2 Neurological status………………………………………………………………37
2.1.2.3 Quality of life…………………………………………………………………….37
2.1.2.4 TXA safety………………………………………………………………………..37
2.2 STUDY DESIGN…………………………………………………………………...38
2.2.1 STUDY DURATION AND TIMELINE………………………………………..38
2.2.2 RESEARCH ETHICS BOARD AND HEALTH CANADA APPROVAL…….41
2.3 PARTICIPANT ELIGIBILITY AND RECRUITMENT………………………..41
2.3.1 INCLUSION CRITERIA………………………………………………………..41
2.3.2 EXCLUSION CRITERIA……………………………………………………….42
2.3.3 PATIENT SCREENING AND DETERMINING PATIENT ELIGIBILITY…..43
2.3.4 PARTICIPANT RECRUITMENT………………………………………………43
2.3.5 PARTICIPANT RANDOMIZATION…………………………………………..44
2.4 STUDY DRUG……………………………………………………………………...44
2.4.1 TXA DOSING REGIMEN………………………………………………………44
2.4.2 TXA DISPENSING PROCEDURES…………………………………………....46
2.4.3 MONITORING STUDY DRUG COMPLIANCE………………………………46
3. STUDY METHODS………………………………………………………………..47
3.1 DATA COLLECTION……………………………………………………………..47
3.1.1 STUDY FEASIBILITY DATA………………………………………………….47
3.1.2 RADIOLOGIC DATA…………………………………………………………..47
3.1.2.1 Hematoma volume calculation…………………………………………………..47
3.1.2.2 Other radiologic variables………………………………………………………51
3.1.3 NEUROLOGICAL TESTS AND ASSESSMENTS…………………………….53
3.1.3.1 Glasgow Coma Scale…………………………………………………………….53
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3.1.3.2 Glasgow Outcome Scale-Extended………………………………………………53
3.1.3.3 Markwalder Grading Score……………………………………………………...54
3.1.3.4 modified Rankin Scale…………………………………………………………...54
3.1.3.5 National Institutes of Health Stroke Scale……………………………………….54
3.1.4 QUALITY OF LIFE (QOL) MEASURES………………………………………55
3.1.4.1 SF-36…………………………………………………………………………….55
3.1.4.1.1 SF-36 questionnaire overview……………………………………………….55
3.1.4.1.2 Scoring of the SF-36…………………………………………………………56
3.1.4.2 HUI……………………………………………………………………………....56
3.1.4.2.1 HUI questionnaire overview…………………………………………………56
3.1.4.2.2 Scoring of the HUI questionnaire……………………………………………57
3.2 CASE REPORT FORM AND DATA COLLECTION MONITORING………59
3.3 SAFETY MONITORING…………………………………………………………60
3.3.1 LABORATORY TESTS………………………………………………………...60
3.3.2 OPHTHALMOLOGICAL EVALUATIONS…………………………………...60
3.3.3 MONITORING AND MANAGING ADVERSE EVENTS AND ADVERSE
DRUG REACTIONS……………………………………………………………61
3.4 STUDY ENDPOINTS, PARTICIPANT DISCONTINUATION, AND
PARTICIPANT WITHDRAWAL………………………………………………...61
3.5 DATA ANALYSIS…………………………………………………………………62
3.5.1 STATISTICAL TESTS…………………………………………………………62
3.5.2 SAMPLE SIZE CALCULATION………………………………………………62
4. RESULTS……………………………………………………………………….….63
4.1 CONSORT FLOW DIAGRAM…………………………………………………..63
4.2 PARTICIPANT RECRUITMENT AND STUDY FEASIBILITY……………...64
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4.3 BASELINE DEMOGRAPHICS AND CLINICAL CHARACTERISTICS……67
4.4 RADIOLOGIC SUBDURAL HEMATOMA FEATURES……………………...69
4.4.1 BASELINE RADIOLOGIC CHARACTERISTICS……………………………69
4.4.2 HEMATOMA VOLUME CHANGE OVER STUDY COURSE……………….71
4.4.3 HEMATOMA RECURRENCE RATE AND NEED FOR REOPERATION…..74
4.5 NEUROLOGICAL STATUS ASSESSMENTS AT BASELINE AND 4-8 WEEK
FOLLOW-UP………………………………………………………………………75
4.6 QUALITY OF LIFE ASSESSMENT SCORES AT BASELINE AND
FOLLOW-UP………………………………………………………………………78
4.6.1 SF-36 QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK
FOLLOW-UP……………………………………………………………………79
4.6.2 HUI QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK
FOLLOW-UP……………………………………………………………………80
4.6.2.1 HUI Mark 3……………………………………………………………………...80
4.6.2.2 HUI Mark 2……………………………………………………………………...85
4.7 ADVERSE EVENTS AND TXA SAFETY……………………………………….89
5. DISCUSSION…………………………………………………………………….....91
5.1 BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS……..91
5.2 RADIOLOGIC SUBDURAL HEMATOMA CHARACTERISTICS…………..92
5.3 PRIMARY OUTCOME……………………………………………………………92
5.3.1 STUDY FEASIBILITY AND RECRUITMENT RATE………………………..92
5.3.2 STUDY DRUG COMPLIANCE AND OUTCOME MEASURE
COMPLETION………………………………………………………………….98
5.4 SECONDARY OUTCOMES……………………………………………………..100
5.4.1 HEMATOMA VOLUME CHANGE FROM BASELINE TO FOLLOW-UP..100
5.4.2 HEMATOMA RECURRENCE AND REOPERATION RATE………………101
5.4.3 NEUROLOGICAL STATUS FROM BASELINE TO FOLLOW-UP………..102
5.4.4 QUALITY OF LIFE FROM BASELINE TO FOLLOW-UP…………………104
5.4.4.1 SF-36…………………………………………………………………………...104
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5.4.4.2 HUI……………………………………………………………………………..104
5.4.5 TXA SAFETY: ADVERSE EVENTS AND SAFETY OF TXA DOSING
REGIMEN……………………………………………………………………...106
5.5 STUDY LIMITATIONS………………………………………………………….109
6. CONCLUSIONS…………………………………………………………………..113
7. FUTURE DIRECTIONS…………………………………………………………114
7.1 DOUBLE-BLINDED EFFICACY TRIAL……………………………………...114
7.2 SCOPING REVIEW OF CSDH PATHOGENESIS……………………………115
7.3 DEVELOPING A PROGNOSTIC MODEL TO ESTIMATE RISK OF CSDH
RECURRENCE…………………………………………………………………..118
7.4 INVESTIGATING CSDH PATHOGENESIS………………………………….119
8. REFERENCES…………………………………………………………………...120
9. APPENDICES…………………………………………………………………….137
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ABBREVIATIONS ACE angiotensin converting enzyme ADR adverse drug reactions AE adverse event ANCOVA analysis of covariance APTT activated partial thromboplastin time ASA acetylsalicylic acid BBB blood-brain barrier bFGF basic fibroblast growth factor BHC burr-hole craniostomy BID bis in die (twice a day) bCSDH bilateral chronic subdural hematoma CAD coronary artery disease CD31 Cluster of differentiation 31 protein COX-1 cyclooxygenase-1 COX-2 cyclooxygenase-2 CRF case report form CSDH chronic subdural hematoma CSF cerebrospinal fluid CT computed tomography eGFR estimated glomerular filtration rate ELISA enzyme-linked immunosorbent assay FDP fibrin degradation product FEIBA factor eight inhibitor bypassing activity GCS Glasgow Coma Scale GFR glomerular filtration rate GOS Glasgow Outcome Score GOSE Glasgow Outcome Scale-Extended H&E hematoxylin and eosin HGF hepatocyte growth factor HRQL health-related quality of life HUI2 Health Utilities Index Mark 2 HUI3 Health Utilities Index Mark 3 ICH intracranial hemorrhage IFA intravenous fluid administration IL-1E interleukin 1 beta IL-2R interleukin 2R IL-4 interleukin 4 IL-5 interleukin 5 IL-6 interleukin 6 IL-7 interleukin 7 IL-8 interleukin 8 IL-10 interleukin 10 IL-13 interleukin 13
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INR International Normalized Ratio IP investigational product MeSH medical subject heading MGS Markwalder Grading Score MMP matrix metalloproteinase mRS modified Rankin Scale MVD microvessel density NIHSS National Institutes of Health Stroke Scale PAF platelet activating factor PCC prothrombin complex concentrate PECAM-1 Platelet endothelial cell adhesion molecule PGE2 prostaglandin-E2 PI Principal Investigator POA power of attorney PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses PT prothrombin time QOL quality of life RCT randomized controlled trial REB Research Ethics Board SAE serious adverse event SAH subarachnoid hemorrhage SDH subdural hematoma SDM substitute decision maker SF-36 RAND 36-Item Short Form Health Survey 1.0 SMD standardized mean difference RN registered nurse SOP Standard Operating Procedures STD standard deviation TID ter in die (three times a day) TNF-D tumor necrosis factor alpha tPA tissue plasminogen activator VEGF vascular endothelial growth factor VP ventroperitoneal
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LIST OF TABLES
Table 1. Variables collected at each in-hospital and telephone follow-up for study duration
Table 2. TXA dose administration schedule according to bodyweight
Table 3. Subdural hematoma radiologic sub-classification system
Table 4. Baseline demographic and clinical characteristics
Table 5. Radiologic hematoma characteristics at baseline
Table 6. Procedure type and hematoma volume change over study course
Table 7. Neurological status at baseline and 4-8 week follow-up
Table 8. Neurological status change from baseline to 4-8-week follow-up
Table 9. SF-36 scores at baseline and 4-8 week follow-up
Table 10. Change in SF-36 scores from baseline to 4-8-week follow-up
Table 11. Frequency distribution of HUI3 single-attribute levels
Table 12. Mean overall HUI3 multi-attribute HRQL utility scores
Table 13. Change in overall HUI3 multi-attribute HRQL utility scores
Table 14. Frequency distribution of disability category based on overall HUI3 Multi-
attribute (HRQL) Utility Scores at baseline
Table 15. Frequency distribution of HUI2 single-attribute levels
Table 16. Mean overall HUI2 multi-attribute HRQL utility scores
Table 17. Change in overall HUI2 multi-attribute HRQL utility scores
Table 18. Frequency distribution of disability category based on overall HUI2 Multi-
attribute (HRQL) Utility Scores at baseline
Table 19. Frequency of adverse events and serious adverse events
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LIST OF FIGURES
Figure 1. Illustration of chronic subdural hematoma (CSDH)
Figure 2. Subdural hematomas on CT imaging
Figure 3. The coagulation cascade
Figure 4. The fibrinolytic cascade
Figure 5. Mechanism of action of Tranexamic Acid (TXA)
Figure 6. Timeline of study follow-up visits and phone calls
Figure 7. Hematoma tracing technique and measurement of other radiologic features using
the Carestream PACS viewer
Figure 8. CONSORT flow diagram
Figure 9. Most common reasons for patient ineligibility
Figure 10. Cumulative participant recruitment
Figure 11. Recruitment per month
Figure 12. Proportion of eligible patients per month
Figure 13. Mean hematoma volume over time
Figure 14. Frequency distribution of overall HUI3 Multi-attribute (HRQL) Utility Scores
Figure 15. Frequency distribution of overall HUI2 Multi-attribute (HRQL) Utility Scores
Figure 16. PRISMA Flowchart
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LIST OF APPENDICES
APPENDIX A: Glasgow Coma Scale
APPENDIX B: Glasgow Coma Scale-Extended
APPENDIX C: Markwalder Grading Score
APPENDIX D: modified Rankin Scale
APPENDIX E: HUI Mark 3 (HUI3) and HUI Mark 2 (HUI2) Classification Systems
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1. INTRODUCTION AND LITERATURE REVIEW
1.1 CHRONIC SUBDURAL HEMATOMA: THE CLINICAL PICTURE AND
CURRENT STANDARD OF CARE
1.1.1 WHAT IS A CHRONIC SUBDURAL HEMATOMA?
Chronic subdural hematoma (CSDH) is one of the most frequently encountered
neurosurgical conditions, with an incidence of 13.5 persons per 100,000 (Almenawer et al.,
2014). This condition predominantly affects older individuals, with the average patient age at
time of occurrence reported to range between 63-81 years old (Asghar, Adhiyaman,
Greenway, Bhowmick, & Bates, 2002; Lee, Ebel, Ernestus, & Klug, 2004). In individuals
over the age of 65, the incidence is much higher, at 58.1 per 100,000 (Almenawer et al.,
2014). Due to the unprecedentedly rapid rate of aging of our population, this incidence is
projected to more than double in the next decade (Santarius, Kirkpatrick, Kolias, &
Hutchinson, 2010).
1.1.2 RELEVANT NEUROANATOMY AND FORMATION OF A CHRONIC
SUBDURAL HEMATOMA
In order to understand the clinical presentation and health implications of CSDH, as well as
risk factors for its occurrence, it is important to first understand the pertinent neuroanatomy.
The brain is surrounded by three tissue coverings called meninges. Directly attached to the
brain tissue is the thinnest covering, called the pia mater. Above the pia is a second, thicker
meningeal layer, called the arachnoid mater. There is a space between the pia and arachnoid
mater, called the subarachnoid space, where cerebrospinal fluid (CSF) collects and from
which its constituents are absorbed into the venous circulation for recycling. Finally, the
third and thickest meningeal covering, the dura mater, is above and directly adjacent to the
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arachnoid mater. Unlike the subarachnoid space between the pia and arachnoid, no space
exists between the arachnoid and dura unless a space-occupying mass grows or fluid
collection occurs. It is therefore termed a potential space, as there exists a possibility of a
space forming.
The dura mater – Latin for hard mother – is a thick, fibrous tissue composed of two layers:
the meningeal dura mater, which is adjacent to the arachnoid mater, and the periosteal dura
mater, which is adjacent to the skull. In some areas of the cranial cavity, these layers separate
to form dural venous sinuses, where deoxygenated venous blood from the brain is collected
and returned to the venous circulation for reoxygenation. In order to drain the brain of
deoxygenated blood, blood vessels called bridging veins carry blood from the brain tissue to
these dural sinuses, and traverse the meninges in order to do so. Given their position, a tear in
a bridging vein can result in a slow accumulation of venous blood into the potential subdural
space between the meningeal dura and arachnoid mater, forming a collection of blood called
a hematoma (Figure 1).
Figure 1. Illustration of chronic subdural hematoma (CSDH). When trauma causes bridging veins to tear, venous blood accumulates between the meningeal dura and arachnoid mater, forming a subdural hematoma. Illustration by Adriana M. Workewych.
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Subdural hematomas are typically traumatic in nature, resulting usually from a minor form of
head trauma. The hematoma begins as an acute bleed. Usually, fibrinolytic processes lead to
the resorption of the clot in this acute, post-traumatic phase. For unclear reasons however,
this process sometimes fails (particularly in senior populations), and the clot is not always
resorbed. Instead, over the course of weeks to months the clot breaks down, leading to a
liquefied or partially liquefied collection of blood in the subdural space, and what is
clinically and radiographically classified as a chronic subdural hematoma.
1.1.3 ETIOLOGY, DEMOGRAPHICS AND CLINICAL PRESENTATION
The presentation of patients with CSDH varies in symptoms reported and severity of those
symptoms. Most patients report having experienced headache for several days to weeks prior
to presenting to the emergency room. Other presenting symptoms include confusion,
memory problems, speech and word-finding difficulties, behavioural changes (pseudo-
dementia), lethargy, gait instability and balance problems, and hemiparesis (Liu, Bakker, &
Groen, 2014a). In rare cases, patients may present with seizure or coma. These symptoms
arise from mass-effects of the enlarging hematoma on the brain.
1.1.4 RISK FACTORS FOR DEVELOPMENT
The major risk factor for CSDH development is age. As we age, brain tissue atrophies,
resulting in an overall shrinkage of brain volume. This shrinkage creates tension on bridging
veins. An accelerating force to the head, or even to the body that causes a rapid acceleration
of the head, causes these blood vessels to tear, leading to the formation of the hematoma.
A history of previous head trauma is present in more than 60% of CSDH cases (Sousa et al.,
2013). Including unreported cases of mild head injury, head trauma is considered one of the
major risk factors for CSDH. Senior populations also have increased susceptibility to falls
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due to balance and gait instabilities, increasing the risk of a minor head trauma event that
leads to a subdural bleed.
However, they may also develop spontaneously, with either an idiopathic origin, or as a
result of an existing medical condition. Patients who develop spontaneous intracranial
hypotension as a result of a cerebrospinal fluid leak are at increased risk of developing a
CSDH (Xia et al., 2015). Patients with a pressure-adjustable ventroperitoneal (VP) shunt
placed for hydrocephalus are likewise susceptible to intracranial hypotension and therefore at
increased risk for developing a CSDH.
Coagulation disorders or the use of anticoagulant or antiplatelet medications are significant
risk factors for CSDH (Sim, Min, Lee, Kim, & Kim, 2012). Seniors in particular are more
likely to be taking anticoagulant and antiplatelet medications for other comorbidities, such as
atrial fibrillation, coronary artery disease, or hypertension. The incidence of CSDH in
chronic renal-dialysis patients, for instance, is about ten-times higher than the general
population (Sood, Sinson, & Cohen, 2007). These patients are more likely to experience
venous hypertension, which, in addition to the anticoagulation therapy administered during
the dialysis procedure, increases the risk of subdural hematoma formation.
Another risk factor is prolonged alcohol abuse, not only because it induces brain atrophy,
liver cirrhosis with associated impairment of coagulation, but because it is more likely to
lead to unrecognized head trauma events (Sim et al., 2012). Seizures and epilepsy are also
recognized risk factors for CSDH (Balser et al., 2013; Sim et al., 2012).
1.1.5 SUBDURAL HEMATOMA APPEARANCE ON AND SUBTYPE
CLASSIFICATION WITH DIAGNOSTIC IMAGING
The standard imaging technique for radiologically investigating a subdural hematoma is
computed tomography (CT) scan. On CT imaging, a subdural hematoma appears as an extra-
axial, crescent-shaped collection of blood between the dura mater and arachnoid mater
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(Figure 2). An acute subdural hematoma appears hyperdense on CT imaging. After several
days to weeks of clot liquefaction, the hematoma begins to appear isodense (Figure 2A)
compared to the surrounding brain tissue. Clinically, this is referred to as a subacute
hematoma. After several weeks to months of continued clot liquefaction, the hematoma
appears hypodense with respect to the brain parenchyma (Figure 2A). The fibrous outer
membrane appears hyperdense, and depending on its thickness, may or may not be visible on
imaging. Calcifications may also form within the outer membrane, appearing as
hyperdensities on a CT scan.
Depending on the age of the hematoma, degree of clot breakdown, and presence of one or
more fibrous membranes, the hematoma can appear homogenous (that is, uniform in
density), or heterogenous (mixed-density) (Figure 2B). If acute bleeds, perhaps resulting
from a second traumatic event or microbleeds from the surrounding membrane, contribute to
the existing liquefied hematoma, both hypodense and hyperdense components would appear
on CT imaging. Clinically, this is referred to as an acute-on-chronic hematoma. Mixed
density hematomas often appear as separated with fluid-fluid levels, with a hypodense
component sitting above a hyperdense component.
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A. B.
Figure 2. Subdural hematomas on CT imaging (from left to right) A. Bilateral, homogenous chronic subdural hematomas: right hematoma appears hypodense relative to brain tissue, and left hematoma appears isodense relative to brain tissue on CT scan. B. Heterogenous (mixed-density) left-sided subdural hematoma, with hypodense, hyperdense, and isodense fluid components, traversed by loculations and septations.
Hematomas can also appear septated, or loculated, as a result of the formation of several
membranes traversing the hematoma, separating the hematoma into several compartments
rather than one uniform bleed.
Due to the mass effect of the hematoma on the surrounding brain tissue, several radiologic
features can also be noted on imaging. Often, mass effects of the hematoma cause effacement
of the surrounding sulci. Unilateral hematomas in particular often result in a midline shift as
a result of increasing intracranial pressure. Finally, while most hematomas are unilateral, up
to 25% of cases are bilateral (Y.-H. Huang, Yang, Lee, & Liao, 2013), which do not always
cause a large midline shift. The degree of midline shift is a useful indicator of patient
prognosis, and may be associated with other symptoms of intracranial hypertension, such as
7
brain tissue herniation and hydrocephalus.
1.1.6 SURGICAL EVACUATION IS THE STANDARD TREATMENT FOR CSDH
On occasion, spontaneous resolution of CSDHs has been reported (Rohde, Graf, & Hassler,
2002). However, due to the fact that an enlarging hematoma places increasing pressure on
surrounding brain tissue, surgical evacuation is the preferred treatment, particularly for
symptomatic hematomas. Medical interventions, while previously explored, were quickly
considered inferior to surgical intervention.
The current standard treatment for CSDH is surgical evacuation (Regan, Worley, Shelburne,
Pullarkat, & Watson, 2015). At most neurosurgical institutions, the preferred approach is
burr-hole craniostomy (BHC) to evacuate the hematoma. This technique is minimally-
invasive compared to a larger craniotomy, thereby substantially mitigating the risk of
morbidity and mortality from a more extensive neurosurgical procedure. A retrospective
review of 119 patients who underwent surgical evacuation of at least one CSDH – 58 by
craniotomy and 61 by burr-hole craniostomy – reported better clinical outcome in patients
who underwent burr-hole drainage (Regan, Worley, Shelburne, Pullarkat, Watson, et al.,
2015). Performed either under general or local anesthesia, the surgeon creates a burr-hole in
the skull overlying the hematoma, opening the dura mater, draining the hematoma and
flushing out the space with saline solution. Before closure, a closed-system drain is placed in
the subdural space to continue drainage for typically up to 24 hours after surgery, and is then
removed. Depending on the size and laterality of the hematoma, more than one burr-hole is
made, though there are inconsistent findings as to the ideal number of burr-holes (Kansal,
Nadkarni, & Goel, 2010; Taussky, Fandino, & Landolt, 2008). Further, depending on the
nature and density of the hematoma, a mini-craniotomy may be fashioned by expanding the
size of the burr-hole with a craniotome. This larger cranial opening is usually preferred when
the hematoma is septated by fibrous membranes, which need to be removed to evacuate the
entire hematoma (membranectomy) (Rohde et al., 2002).
8
Patients typically remain in hospital for several days following the procedure. The symptoms
experienced prior to surgery are usually relieved by surgery. However, symptoms may
persist as a result of incomplete hematoma evacuation and persisting mass effects. Post-
operative care includes an assessment by physiotherapy and occupational therapy to assess
patient mobility, as some patients may require rehabilitation to return to their previous level
of functionality. In a large prospective cohort study of 823 surgically-treated CSDH patients,
47% were transferred to an outside institution for ongoing care and 49% were discharged
home (Brennan et al., 2017). They also reported a 2% mortality rate.
1.1.7 SURGICAL AND MEDICAL COMPLICATIONS AFTER SURGICAL
EVACUATION
In neurosurgical terms, burr-hole evacuation is a minor procedure, and surgery-related
complications are rarely reported (Mori & Maeda, 2001). Complications do occur, however,
and given their contribution to overall mortality, their clinical significance cannot be
neglected. Seizures are one of the most common minor complications experienced after BHC
with closed-system drainage, and in some cases may persist for some time (Rohde et al.,
2002). Major complications include subdural empyema and intracranial hemorrhage (Rohde
et al., 2002).
Due to the advanced age of this patient population, many have concurrent medical
conditions, which increase their susceptibility to medical complications after surgery.
Complications often include infection and seizures (Rohde et al., 2002). Mortality from
medical complications after burr-hole evacuation is higher than from surgical complications
(Rohde et al., 2002).
Patients are typically discharged home, or referred to a rehabilitation center if they are
experiencing physical, cognitive, or speech impairment that requires the services of a
physical therapist or speech pathologist. Several weeks after surgery, patients undergo a
9
repeat CT scan and clinical examination with their neurosurgeon to evaluate the resolution of
the hematoma and their subsequent clinical status.
1.2 THE CLINICAL PROBLEM: POST-OPERATIVE HEMATOMA
RECURRENCE
After hematoma evacuation, the brain does not immediately re-expand to fill the space left
by the hematoma. Consequentially, hematoma remnants – both liquid and fibrous – typically
remain in this space, presenting the potential for re-accumulation of the hematoma. The rate
of recurrence reported in the literature is somewhat variable; 3-31% of patients experience a
re-accumulation of their CSDH after initial surgical evacuation, requiring reoperation (Rohde
et al., 2002). Repeated surgery is associated with increased risk of morbidity and mortality,
including pneumonia or other infection, stroke, intracerebral hemorrhage, and seizure (Mori
& Maeda, 2001). This is particularly concerning in elderly patients, who are more susceptible
to medical complications after surgery (Rohde et al., 2002). The potential risks associated
with repeated surgical intervention therefore cannot be discounted as insignificant (Nayil et
al., 2012).
1.2.1 DEMOGRAPHIC, CLINICAL, OPERATIVE, AND RADIOLOGIC
PREDICTORS OF POST-OPERATIVE CSDH RECURRENCE
Research with regards to identifying predictors of recurrence has been largely inconclusive,
with focus placed primarily on the type of surgical intervention (specifically, the size of the
cranial opening, either a burr-hole or mini-craniotomy), the duration of post-operative drain
placement, the use of anticoagulants, age and gender. Previously reported causative factors
include advanced age (Han et al., 2016), preoperative antiplatelet therapy (Wada et al., 2014)
(though this evidence is inconsistent (Aspegren, Åstrand, Lundgren, & Romner, 2013)),
shorter duration of post-operative drainage (Song et al., 2014), bilateral vs unilateral
hematoma site (Q. Huang et al., 2009; C.-C. Lin et al., 2014; Song et al., 2014), larger post-
10
operative hematoma volume (F.-F. Xu et al., 2014), and separated/layered type hematomas
(Y.-H. Huang, Lin, Lu, & Chen, 2014; C.-C. Lin et al., 2014). Pre-operative volume has not
been significantly associated with recurrence (Y.-H. Huang et al., 2014). No significant
correlation between operative factors (operation type, drain used, anesthetic) and post-op
recurrence has been found (Phang, Sivakumaran, & Papadopoulos, 2015). A meta-analysis of
13 studies suggested decreased risk of recurrence in burr-hole surgery with closed-system
drainage compared to other surgical procedures (C. Xu, Chen, Yuan, & Jing, 2016). No
difference in recurrence rates was identified between burr-hole vs twist drill (Escosa Baé,
Wessling, Salca, & de las Heras Echeverría, 2011; Liu, Bakker, & Groen, 2014b) evacuation,
and inconsistent evidence exists as to whether or not the use of saline irrigation effects post-
operative recurrence (Liu et al., 2014b; C. Xu et al., 2016).
The use of post-operative drainage has fairly consistently been correlated with decreased
recurrence rates (Wada et al., 2014). A systematic review of 297 studies, including 19 RCTs,
reported a decreased risk of recurrence with the use of post-operative drainage (Liu et al.,
2014b). A prospective randomized study of 200 patients surgically treated for CSDH
reported decreased recurrence rate in patients assigned to post-operative drainage compared
to patients without drainage (Singh et al., 2014). Drains were placed for 48-hours in the
drainage group. Nine patients in the drainage group required reoperation for postoperative
hematoma recurrence compared to 26 in the no-drainage group.
A study retrospectively reviewed 209 cases of CSDH admitted to their institution (Miranda,
Braxton, Hobbs, & Quigley, 2011). They primarily investigated the relationship of several
factors – including neurological status upon admission, type of intervention, hematoma size
and anticoagulant use – to survival. The overall mortality rate was 26.3% at six months, and
32% at one-year. They identified neurological status upon hospital admission as the only
predictive factor of in-hospital mortality. The group also reported a 3.6% recurrence rate in
their cohort, and saw no correlation between premorbid anticoagulant use or hematoma
laterality with hematoma recurrence.
11
Berghauser Pont et al (Berghauser Pont, Dammers, Schouten, Lingsma, & Dirven, 2012)
performed a retrospective review of 496 consecutive SDH patients treated with burr hole
craniostomy over 18 years (1990-2008) at a single institution. All patients were treated
preoperatively with 4 mg dexamethasone 4 times daily for at least 2 days. Prolonged
preoperative corticosteroid use, and Glasgow Coma Scale (GCS) motor score were identified
as independent predictors of recurrence.
Janowski et al (Janowski & Kunert, 2012) focused on investigating post-operative
interventions with potential to prevent recurrence. They investigated post-operative
intravenous fluid administration (IFA), and performed a univariate regression analysis
demonstrated that IFA independently influenced hematoma recurrence rate and Glasgow
Outcome Score (GOS), a measure of cognitive status.
Chon et al, 2012 (Chon, Lee, Koh, & Choi, 2012a) also aimed to investigate individual
predictors of recurrence. They retrospectively evaluated 420 patients and identified a 21.9%
recurrence rate. The authors identified independent radiologic and clinical predictors of
recurrence, including postoperative midline shifting (≥5 mm), diabetes mellitus,
preoperative seizure, preoperative width of hematoma (≥20 mm), and use of anticoagulant
therapy.
Stanisic et al, (Stanišić et al., 2013b) retrospectively reviewed 107 patients, finding a 15.9%
recurrence rate. They identified several radiological predictors of recurrence, including:
preoperative hematoma volume and the residual total hematoma cavity volume on the first
postoperative day after drain removal.
Tugcu et al, (Tugcu et al., 2013) aimed to determine predictors of recurrence after single
burr-hole for hematoma evacuation. In their retrospective review of 292 CSDH patients, they
identified a 14.7% recurrence rate. They identified a single predictor of recurrence: bilateral
subdural hematoma. They also looked at age, gender, hypertension, diabetes mellitus,
preceding head trauma, the time interval between trauma and the operation, and previous
12
anticoagulant and anti-platelet therapy, but saw no association with these factors and
hematoma recurrence.
Xu et al (F.-F. Xu et al., 2014) prospectively studied 54 SDH patients, and focused on
association between CT features and recurrence. They identified that a higher recurrence rate
was associated with greater pre-operative (over 120 ml) and/or pre-discharge subdural fluid
volumes (over 22 ml), and larger pre-operative (over 15.1 mm) and/or residual (over
11.7 mm) SDH widths. Changes in residual volume during the acute resolution period were
also identified as radiological predictors of recurrence.
Jung et al (Jung, Jung, & Kim, 2015) aimed to determine predictors of recurrence after burr-
hole trephination. In their retrospective chart and CT review of 182 patients, they saw a
13.7% recurrence rate. They found that recurrence correlated with midline displacement of
more than 10 mm and clinical presentation of hemiparesis.
Leroy et al (Leroy et al., 2015) retrospectively reviewed 140 consecutive cases of SDH.
Multivariate analyses showed an association between increased risk of poor functional
outcome and advanced age, residual hematoma thickness >14 mm, and GCS < 15. They
identified a 17% recurrence rate. Independent predictors of recurrence were preoperative
anticoagulant therapy and persistent mass effect on postoperative CT imaging.
Schwarz et al (Schwarz et al., 2015) retrospectively reviewed 193 patients who underwent
burr-hole trephination for SDH evacuation. They identified an 18.1% recurrence rate.
Midline shift, arterial hypertension, and bilateral hematomas were identified as risk factors
for recurrence. While no correlation was found, the authors also looked at demographic
factors, comorbidities, medications, symptom presentation, trauma, and some features on CT
(midline shift, size, bleeding, membranes, density).
Andersen-Ranberg et al (Andersen-Ranberg, Poulsen, Bergholt, Hundsholt, & Fugleholm,
2017) looked at independent predictors of recurrence specifically for bilateral CSDH
(bCSDH). They performed a retrospective review of 291 patients with bCSDH who
13
underwent either unilateral or bilateral burr holes. Overall there was a 21.6% recurrence rate,
and absence of post-operative drainage, and unilateral burr-hole for bilateral hematoma were
identified as predictors of recurrence.
1.2.2 RADIOLOGIC HEMATOMA SUBTYPES AS PREDICTORS OF
RECURRENCE
Nakaguchi et al (2001) proposed a classification system for CSDH based on hematoma
density and radiographic characteristics, as seen on CT imaging. They classified CSDH into
four subtypes: Homogenous (uniform density); Laminar (uniform density with a thin hyper-
density along inner membrane); Separated (two densities with a clear separation, with the
hypodense component above the hyperdense component); and Trabecular (heterogenous
densities, with hyperdense septation traversing from the outer to the inner membrane). They
further went on to classify the progression of hematoma development through these subtype
classifications, proposing that a CSDH may originate as a homogenous type, progress into
the laminar type, mature into the separated stage, and finally undergo absorption during the
trabecular stage (Nakaguchi, Tanishima, & Yoshimasu, 2001).
Several studies have proceeded to use the Nakaguchi classification system to identify
radiologic hematoma features that may predict recurrence. Chon et al. saw significantly
lower recurrence rates in homogenous and trabecular subtypes, compared to laminar and
separated subtypes (Chon, Lee, Koh, & Choi, 2012b). Ohba et al. later reported that the
separated hematoma type was significantly more closely related to recurrence when
compared to the laminar subtype (Ohba, Kinoshita, Nakagawa, & Murakami, 2013).
Stanisic et al. (Stanišić & Pripp, 2017) and Jack et al. (Jack, O’Kelly, McDougall, & Max
Findlay, 2015)created grading systems using radiologic hematoma features as predictors of
recurrence requiring reoperation, though more work is needed in this field to arrive at an
accurate prediction of recurrence.
14
1.3 PATHOGENESIS AND THE MECHANISM OF CSDH ENLARGEMENT
The exact mechanism of CSDH development and enlargement is not entirely clear, though it
is likely that several mechanisms work in tandem to cause the chronification of the initially
acute bleed. Elucidating the pathogenic mechanism is crucial for determining biomarkers that
may predict hematoma recurrence or clinical outcome, but also for identifying potential
therapeutic targets. The most well supported theories for CSDH development and
enlargement emphasize osmolarity, inflammation, angiogenesis, and hyperfibrinolysis as
central mechanisms.
1.3.1 OSMOLARITY
Bradykinin, an inflammatory factor that causes blood vessel dilation, was found to be
significantly elevated in hematoma fluid compared to blood plasma (Fujisawa, Ito,
Kashiwagi, Nomura, & Toyosawa, 1995). There was also a higher blood protein content in
hematoma fluid. It is possible that these elevated factors together contribute to increased
exudation from capillaries into the hematoma, contributing to its evolution.
1.3.2 INFLAMMATION
In 1657, pathologist Johann Wepfer first identified what he termed a “bloody cyst” in the
subdural space while performing an autopsy on an elderly man who at his time of death was
experiencing aphasia and hemiplegia (Putnam & Cushing, 1925). In 1857, Rudolph Virchow
described a similar case which he termed pachymeningitis hemmorhagica interna, and was
the first to attribute its cause to inflammation (Virchow, 1857). In the following years, the
idea that inflammation was a cause of CSDH development was contested, with emphasis
placed on trauma as a singular cause. However, the role of inflammation was revisited and
today is ubiquitously accepted as a key underlying pathogenic mechanism.
15
Inflammatory responses are necessary for tissue repair, however in CSDH it is believed there
is a pathological and sustained inflammatory response to the presence of blood in the
subdural space (Hong et al., 2009). This likely encourages the formation of a fibrous
membrane, which grows to encapsulate the hematoma. Radiographically and pathologically
the membrane is usually identified as an outer, thicker membrane adjacent to the dura mater,
and an inner membrane adjacent to the arachnoid mater.
One proposed mechanism for hematoma development is that trauma to endothelial tissue and
the meninges leads to the exudation of high levels of inflammatory cytokines into the
subdural space, triggering the acute hematoma to begin to chronify (Frati et al., 2004).
Several studies suggest that inflammatory cytokines and chemokines are mediators of CSDH
development, and play a crucial role in hematoma enlargement (Stanisic, Aasen, et al., 2012;
Stanisic, Lyngstadaas, et al., 2012). This has been additionally corroborated in several
studies that identified elevated levels of pro-inflammatory cytokines, as are discussed below.
Interleukins 6 and 8 (IL-6 and IL-8) were found in greater levels within the hematoma fluid
compared to venous blood (K.-S. Park, Park, Hwang, Kim, & Hwang, 2015). While
investigating the role of cytokines in development of CSDH, another group also found higher
levels of IL-6, as well as IL-10, thrombomodulin and tumor necrosis factor (TNF)- in
hematoma fluid relative to blood serum (Kitazono et al., 2012). Additional studies saw the
same increase in IL-6 and IL-10, in addition to IL-2R, IL-5, and IL-7, IL-13, in the
hematoma fluid compared to systemic blood levels, while significantly lower levels of TNF-
, IL-1, and IL-4 were present in hematoma fluid (Stanisic, Aasen, et al., 2012; Stanisic,
Lyngstadaas, et al., 2012). Importantly, IL-10 levels were found to be lower in layered
hematoma types with visible membranes, suggesting the possibility that IL-10 deactivates the
inflammatory process in CSDH formation (T. Wada et al., 2006). Furthermore, the ratio
between pro- and anti-inflammatory cytokines was also determined to be significantly higher
in the hematoma fluid than in systemic plasma. These elevated levels of inflammatory
cytokines in the subdural fluid relative to serum provides evidence that the inflammatory
processes involved in hematoma progression are localized to the area of the hematoma,
rather than systemic in nature. Suzuki et al proposed that cytokines in the subdural fluid do
16
not permeate from the blood, rather they are likely synthesized and released in situ from cells
adjacent to the subdural space or from immune cells that have infiltrated the subdural space
(Suzuki, Endo, et al., 1998). Finally, high levels of these cytokines, namely IL-6 and IL-8,
may even predict postoperative hematoma recurrence (Frati et al., 2004).
Additional findings suggesting a role for inflammation in CSDH progression include the
measurement of markedly elevated levels of the inflammatory mediator platelet activating
factor (PAF) in the blood plasma of CSDH patients compared to healthy controls. PAF was
subsequently localized via staining to the outer hematoma membrane, but not the dura
(Hirasima et al., 1994). Hirasima et al proposed that after the formation of a small, initially
acute hematoma following some traumatic force, focal production of PAF occurs in the outer
membrane of the hematoma, initiating the infiltration and subsequent degranulation of
eosinophils into the membrane. Several additional studies, as well as routine pathological
staining, have demonstrated eosinophilic infiltrations within the outer membrane of the
hematoma, supporting inflammation as a pathogenic mechanism for CSDH progression
(Miller, 1990). It is likely that the infiltration of eosinophils into the outer membranes of
CSDHs is important for repair and healing, similar to other chronic inflammatory granulation
tissues. Sarkar et al further observed that the outer membrane was composed of vascularized
and hyalinized fibrocollagenous tissue that was infiltrated with eosinophils in more than half
of their study samples (Sarkar et al., 2002). They also noted that the older the hematoma, the
higher the concentration of eosinophils in the outer membrane. They proposed that
chemotactic stimuli secreted by mast cells as well as lymphocytes may recruit eosinophils to
the membrane. Eosinophils may be recruited to the site of the bleed for their phagocytic role
to aid hematoma reabsorption. Compounding this event, tissue plasminogen activator (tPA)
is released from damaged endothelial cells contributing to local fibrinolysis and possibly
even hyperfibrinolysis. These processes occur in tandem to increase vascular permeability,
leading to repeated bleeding into the hematoma.
17
1.3.3 ANGIOGENESIS
Several studies have implicated vascular endothelial growth factor (VEGF) in the
pathogenesis of CSDH (Nanko et al., 2009; R Weigel, Schilling, & Schmiedek, 2001). In
fact, VEGF as well as its receptors are upregulated after CNS injury. Weigel et al proposed
that high VEGF accumulation in hematoma fluid leads to the continuous formation of
immature, fragile microvasculature in the neomembrane. High VEGF levels also increase
vascular permeability, resulting in higher exudation rates from these microcapillaries. New
hemorrhagic events, in addition to the secretion of plasma components into the hematoma,
result in hematoma enlargement (Ralf Weigel, Hohenstein, & Schilling, 2014). More recent
evidence suggests that high levels of matrix metalloproteinases (MMPs), proteins implicated
in angiogenesis, contribute to high levels of VEGF, which stimulates angiogenesis and
contributes to CSDH development through microbleeds (Hua et al., 2016).
Given the potential role of endothelial factors in CSDH pathogenesis, angiogenic markers
could possibly be used as predictors of recurrence. Hong et al performed
immunohistochemical staining of the outer membrane at the time of initial hematoma
evacuation and saw significantly stronger staining of angiogenic mediators VEGF and basic
fibroblast growth factor (bFGF) in the membranes of patients whose hematomas later
recurred. Given their findings, they suggested that higher concentrations of IL-6 in the
subdural fluid, or enhanced expression of VEGF and bFGF in the outer membrane, may
predict postoperative hematoma recurrence (Hong et al., 2009).
Finally, many proposed theories for CSDH formation combine inflammatory and angiogenic
mechanisms. In addition to finding higher levels of IL-6, IL-8 and VEGF in hematoma fluid
relative to serum, Hara et al also found greater levels of the inflammatory mediator
prostaglandin-E2 (PGE2), a product of cyclooxygenase-1 and -2 (COX-1 and COX-2) pro-
inflammatory enzymatic activity (Hara, Tamaki, Aoyagi, & Ohno, 2009). Staining for COX-
2 in the endothelial cells of sinusoids and capillaries, as well as inflammatory cells, was
positive in the outer membrane but not in the adjacent dura mater. Hara et al thus implicated
COX-2 as a potential contributor to CSDH development. As a result of their findings, they
18
proposed that over-expression of COX-2 in the hematoma outer membrane leads to increased
levels of PGE2 and subsequent overexpression of VEGF, promoting angiogenesis in the
outer membrane, ultimately resulting in immature, leaky blood vessels repeatedly bleed into
the existing hematoma and furthering its enlargement. This proposed theory implicated the
administration of COX-2 inhibitors as a potential medical intervention for CSDH.
1.3.4 HYPERFIBRINOLYSIS
In order to introduce hyperfibrinolysis as a potential mechanism in CSDH formation, it is
first important to briefly summarize the coagulation and fibrinolytic cascades. The
coagulation cascade is initiated when there is damage to a blood vessel, such as tearing to
bridging veins as a result of head trauma (Figure 3). The initial stage in repair is the
formation of a temporary platelet plug at the side of vascular endothelial tissue damage.
Prothrombinase (blood clotting factor Xa and Va) catalyzes the activation of prothrombin to
thrombin (factor IIa), which subsequently catalyzes the conversion of fibrinogen to its active
form fibrin (factor Ia). Active fibrin molecules have a high affinity for one another, leading
to polymerization. Factor XIII cross-links thrombin monomers, resulting in the formation of
a stable fibrin clot. This hemostatic seal prevents re-hemorrhaging during tissue repair, and is
maintained through a careful balance between fibrin formation and fibrin breakdown, or
fibrinolysis.
19
Figure 3. The coagulation cascade. Trauma and damage to endothelial cells leads to the release of factors that triggers the coagulation cascade, eventually resulting in the formation of a cross-linked fibrin clot. Illustration by Adriana M. Workewych.
Fibrinolysis is initiated when vascular endothelial cells release tissue plasminogen activator
(tPA) (Figure 4). The inactive molecule plasminogen first binds to fibrin molecules,
followed subsequently by tPA binding to plasminogen and catalyzing its conversion to the
active form plasmin. Plasmin hydrolyzes fibrin polymers, leaving fibrin degradation products
(FDPs) and causing clot breakdown. Plasmin also degrades fibrinogen, the precursor to
fibrin. This contributes to the low levels of fibrinogen seen in patients with subdural
hematoma (Fujisawa et al., 1995; S.-H. Park et al., 2011).
20
Figure 4. The fibrinolytic cascade. Tissue plasminogen activator (tPA) catalyzes the conversion of plasminogen to plasmin, forming a complex that degrades fibrin clots into fibrin degradation products. Illustration by Adriana M. Workewych.
Though the reason remains unclear, should an imbalance occur between coagulation and
fibrinolysis there is a rapidly excessive dissolution of the blood clot, a process called
hyperfibrinolysis. There is substantial evidence to suggest local hyperfibrinolysis is central to
CSDH formation. Several studies have shown that tissue plasminogen activator (tPA) is
elevated in hematoma fluid (Ito, Komai, & Yamamoto, 1978), and was found to be
particularly elevated in layered-type, multi-membrane hematomas (Fujisawa et al., 1991; Ito,
Saito, Yamamoto, & Hasegawa, 1988). While normal tPA production leads to the absorption
of subdural blood and ultimately hematoma resolution, overproduction of tPA over an
extended period of time leads to hyperfibrinolysis, and therefore excessively rapid clot
dissolution. Based on findings involving the fibrinolytic cascade, Ito et al. proposed a
mechanism for hematoma formation: an initially acute hemorrhage in the subdural space
becomes encapsulated by a fibrous membrane, which releases tPA. High levels of tPA,
released from the outer hematoma membrane, diffuse into the hematoma, catalyzing the
conversion of plasminogen to plasmin, thereby increasing the levels of fibrin degradation
products (FDP). Elevated levels of FDP interfere with homeostasis of the blood clotting
21
process, leading to a progressive enlargement of the hematoma, and presumably also
degrading the clot, leading to rebleeding from the original vessel. Another group measured
high levels of plasminogen and low levels of antiplasmin, an inactivator of plasmin, in the
hematoma fluid, contributing to elevated levels of plasmin and therefore overproduction of
FDPs (Weir & Gordon, 1983).
Similarly, Suzuki et al. theorized that following a head injury, both blood and cerebrospinal
fluid collect in the subdural space (Suzuki, Kudo, et al., 1998). Prothrombin is activated to
thrombin and endothelial tissue damage triggers the recruitment of fibroblasts and
inflammatory cells, which lead to the formation of the outer hematoma membrane.
Angiogenesis in this outer membrane leads to the formation of immature capillaries which
repeatedly rupture, releasing tPA from the damaged epithelial cells and subsequently
increasing the rate of fibrinolysis. This process repeats itself through recurrent bleeding from
the capillaries, and in this way, the hematoma increases in size.
In addition to its likely role in hematoma enlargement, elevated levels of tPA have also been
identified as a potential predictor of post-operative hematoma recurrence (Katano, 2006).
Katano et al measured higher levels of tPA, as well as 2-antiplasmin, in hematomas that
later recurred compared to non-recurrent hematomas. Both were also found to be higher in
hematoma fluid than blood serum. This was also true for hepatocyte growth factor (HGF)
and VEGF, though these were not identified as predictors of recurrence. From these findings
they also proposed a mechanism of hematoma development: an initial traumatic injury leads
to bleeding and hematoma formation, which triggers an inflammatory response and initial
hypercoagulation. An increase in tPA, as well as eosinophil infiltration and bradykinin
release, leads to co-occurring hyperfibrinolysis, hyperpermeability, and a storm of cytokine
release, as well as elevated VEGF and HGF levels. These processes working in tandem
promote rebleeding into the hematoma, and therefore continued hematoma enlargement.
22
1.3.5 MECHANICAL MECHANISMS
While inflammatory, angiogenic, and hyperfibrinolytic mechanisms likely contribute most
significantly to CSDH development, other mechanical mechanisms may also play a role.
Murakami et al. suggested that pulsation in the hematoma cavity as a result of the pulsating
brain leads to repeated compression and decompression of the outer membrane, causing the
fragile microvessels present within to repeatedly rupture. Thrombomodulin is released,
preventing the healing of injured outer membrane microvessels. This facilitates the process
of recurrent slow bleeding into the hematoma and prevents coagulation, ultimately
contributing to the expansion in hematoma volume (Murakami et al., 2002).
Song et al (2013) hypothesized that when trauma causes damage to the dural border cell
layer, cerebrospinal fluid as well as blood accumulates in the subdural space as foreign
matter, stimulating the inflammatory response and resulting in the secretion of inflammatory
cytokines, VEGF and angiopoietins (Y. Song, Wang, Liu, Wang, & Zhang, 2013). They
proposed that due to an insufficient number of locally circulating endothelial progenitor
cells, the capillaries in the neomembrane harbor structural deficits. This predisposes them to
tearing during abnormal cerebral pulsations, undermining their structural integrity and
physiological repair. A continuous effusion from these pathologically permeable capillaries
into subdural space ensues, leading to CSDH formation and enlargement.
1.4 NON-SURGICAL TREATMENT OF CSDH
Based on the proposed mechanism of hematoma evolution, several medicinal therapies have
and are currently being investigated as either alternatives to surgical evacuation or adjunctive
therapies. Various attempts have been made in past decades to treat CSDH with medications,
including glucocorticoids, angiotensin converting enzyme (ACE) inhibitors, platelet
activating factor inhibitors and traditional Japanese medicines. Unfortunately, there are still
no results from randomized clinical trials to support superiority of any of these treatments to
surgical therapy or any effectiveness over no treatment.
23
In light of the inflammatory hypothesis for CSDH development and progression,
dexamethasone has been explored as an alternative therapy for CSDH. In a placebo-
controlled clinical trial, 20 participants were randomized to receive 12 mg daily of
dexamethasone for 3 weeks or placebo (Prud’homme, Mathieu, Marcotte, & Cottin, 2016).
There were no statistically significant differences in hematoma thickness or other measurable
changes between the two groups over the study period, however, the dexamethasone-treated
group experienced many more side effects and serious adverse events. The small study
sample size, in addition to the high risks of complications associated with dexamethasone
treatment, were insufficient to demonstrate a benefit of dexamethasone treatment compared
to placebo.
Atorvastatin has also been evaluated in CSDH treatment due to its potential anti-
inflammatory mechanism (Qiu et al., 2017). A clinical trial is currently underway to
investigate its efficacy as a safe alternative to surgery (ClinicalTrials.gov Identifier:
NCT02024373) (Jiang et al., 2015).
Poulsen et al. conducted a double-blind, placebo controlled, randomized controlled trial to
investigate the efficacy of perindopril, an angiotensin-converting enzyme (ACE) inhibitor, in
decreasing the risk of CSDH recurrence after burr-hole evacuation (Poulsen, Munthe, Søe, &
Halle, 2014). Of the 47 patients randomized to the study, none experienced a recurrence of
their hematoma within the first six weeks after surgery. Furthermore, there was no significant
difference in residual CSDH size between perindopril-treated and control patients.
One group retrospectively compared the effects of Gorei-san, a commonly used traditional
Japanese medicine, with the effects of TXA for reducing CSDH recurrence after burr-hole
evacuation (Wakabayashi et al., 2012). A total of 199 consecutively admitted patients were
divided into four treatment arms. The lowest recurrence rate was among the patients who
were treated with Gorei-san and TXA. An 8.3% recurrence rate was seen in the Gorei-san-
only treated group. This was compared to a 10.9% recurrence rate in the TXA group, and
24
5.7% recurrence rate in the group that received surgery alone. The differences in recurrence
rates among the four groups did not reach statistical significance.
Kageyama et al. retrospectively reviewed the medical records of 21 patients that were given
oral TXA at a dose of 750 mg daily for the treatment of CSDH (Kageyama, Toyooka,
Tsuzuki, & Oka, 2013). They used CT and magnetic resonance imaging (MRI) throughout
the course of TXA administration to evaluate hematoma volume change. Three patients had
been treated by burr-hole surgery before receiving TXA therapy. All patients experienced a
decrease in total hematoma volume during follow-up, and none of the patients experienced
hematoma recurrence or progression. They proposed that CSDH could be treated with TXA
alone, and without surgical evacuation.
1.5 TRANEXAMIC ACID
Tranexamic Acid (TXA) is an antifibrinolytic drug. That is, it slows the dissolution of clot.
When plasminogen binds to fibrin to initiate clot breakdown, it does so at a lysine binding
site. As a physical analog of lysine, TXA binds to this site on plasminogen, preventing
plasmin from binding to fibrin, thereby preventing the conversion of fibrin to FDPs,
ultimately preventing clot breakdown (Figure 5).
25
Figure 5. Mechanism of action of Tranexamic Acid (TXA). Tissue plasminogen activator (tPA) binds to plasminogen, catalyzing its conversion to plasmin, and forming a complex that binds to lysine binding sites on fibrin, breaking it down into fibrin degradation products (FDPs). Tranexamic Acid (TXA) competes for the lysine binding site, preventing the conversion of plasmin to plasminogen, and ultimately the breakdown of fibrin into FDPs. Illustration by Adriana M. Workewych.
TXA also has low to moderate effects on other enzymatic activity by competitively
inhibiting the activation of trypsinogen, and non-competitively inhibits trypsin (Dubber et al,
1965).
1.5.1 CURRENT THERAPEUTIC INDICATIONS
TXA is widely used in the treatment of congenital bleeding disorders, perioperatively as a
blood-sparing strategy in cardiac and non-cardiac surgery, and in significant trauma with
hemodynamic instability.
26
It has been shown to reduce blood loss in gynecological bleeding disorders, and is commonly
prescribed for abnormal uterine bleeding, most notably menorrhagia (Nilsson & Rybo, 1967,
1971). It has also been shown to be effective in reducing blood loss from post-partum
hemorrhage, as well as bleeding irregularities arising from complications of contraceptive
implants (Gungorduk et al., 2011; Lukes et al., 2010). In a large, international, randomized
controlled trial, 20,060 women diagnosed with post-partum hemorrhage after delivery were
randomized to receive a 1g intravenous dose of TXA or placebo in addition to the standard of
care (WOMAN Trial Collaborators et al., 2017). The results showed a significant reduction
in death due to bleeding in the TXA group compared to controls. Further, the occurrence of
adverse events did not differ between the two groups.
Several randomized controlled trials have shown a significant reduction in perioperative
blood loss after TXA administration compared to placebo controls, namely in cardiac and
orthopedic surgeries, as well as prostatectomies (Later et al., 2009; Sukeik, Alshryda,
Haddad, & Mason, 2011; Zhang, Chen, Chen, & Que, 2012).
Early administration of TXA after injury or trauma has been show to significantly reduce all-
cause mortality and death due to bleeding (CRASH-2 trial collaborators et al., 2010). It is
most effective in reducing mortality if given within the first 60 minutes of injury, with
effectiveness dropping by 10% for every 15-minute delay in time to treatment (I. Roberts,
2015; Ian Roberts et al., 2017).
TXA has also been shown to be an effective therapy in traumatic hyphema, gastrointestinal
bleeding (Ian Roberts et al., 2014), and for symptom relief in angioedema (Wintenberger et
al., 2014).
1.5.2 PHARMACOLOGY
TXA can be administered topically, intravenously, and orally, and is rapidly absorbed after
oral administration. In order to elicit therapeutic effects, the plasma concentration of TXA
27
must be 5-15mg/L (Fiechtner et al., 2001; Katsaros, Petricevic, Snow, Woodhall, & Van
Bergen, 1996; Std, n.d.).
The bioavailability of oral TXA is 40%, and 50% is likely biotransformed by acetylation or
deamination and subsequent oxidation or reduction, resulting in either a dicarboxylic acid or
acetylated products. TXA is renally cleared, with approximately 1% eliminated one hour
after administration, and 39% eliminated after 24 hours.
The terminal elimination half-life of a single oral dose of 1300 mg TXA is approximately
11.1 hours. Pharmacodynamic properties appear to vary slightly according to the indication
for which the drug is used (Dunn & Goa, 1999).
1.5.3 SAFETY
TXA is generally well tolerated. Most reported adverse events in clinical trials are mild or
moderate in severity. Severe or serious adverse events are rare (Leminen & Hurskainen,
2012; McCormack, 2012). Despite this, however, safety concerns regarding TXA include
gastrointestinal symptoms (which typically subside with dose reduction), risk of seizures,
visual disturbances (including impaired visual acuity and color vision), and dizziness.
Isolated and rare cases of thromboembolic events and hypotension have also been reported.
1.5.4 CONTRAINDICATIONS
TXA treatment is contraindicated in patients who exhibit a hypersensitivity to the drug or
any of its ingredients. It is contraindicated in patients who have had a history or have an
increased risk of thrombosis, unless it is possible to administer TXA with anticoagulants, and
as long as there is a strong medical indication for its use, although this contraindication is not
based on the results of clinical studies. Patients with active thromboembolic disease,
including deep vein thrombosis, pulmonary embolism, cerebral thrombosis, and disseminated
28
intravascular coagulation are listed as contraindications to TXA. In some cases, venous and
arterial thrombosis and thromboembolism has been reported in patients being treated with
TXA – however, results from the CRASH-2 trial, as well as a large meta-analysis and other
reviews, show that there is no causative link between the two (CRASH-2 trial collaborators
et al., 2010; Hunt, 2015; Ker, Edwards, Perel, Shakur, & Roberts, 2012). It is not safe for
patients with subarachnoid hemorrhage to be treated with TXA, as the increased risk of
cerebral ischemia outweighs the reduced risk of re-bleeding, according to the product
monograph, as indicated by the product monograph. Patients with hematuria caused by
diseases of the renal parenchyma should not take TXA because of the increased frequency of
intravascular precipitation of fibrin typically seen in this disease. Moreover, in the event of a
renal hemorrhage, antifibrinolytic therapy may increase the risk of clot retention in the renal
pelvis. In one isolated case, a patient developed an insoluble clot obstruction in the renal
pelvis after the administration of epsilon-aminocaproic acid, an anti-fibrinolytic (Wymenga
& van der Boon, 1998).
As advised by the product monograph, TXA therapy should also be discontinued if a patient
experiences colour vision disturbances, as chromatopsia has been reported as a rare case
adverse event after prolonged TXA use. Due to its rarity, the occurrence rate of this adverse
event is not known, however transient colour vision disturbance has been reported as an
isolated adverse event in the post-marketing period (Cravens, Brown, Brown, & Wass,
2006).
1.5.5 WARNINGS AND PRECAUTIONS
Caution while taking TXA is advised in patients with visual disturbances, such as sudden
impaired visual integrity, colour vision, or blurred vision. Convulsions and seizure activity
has been reported in association with TXA treatment, and therefore precautions should be
taken when considering TXA treatment in patients with a history of seizure, or if high doses
are used during high-risk surgeries as a result of disruption of the blood-brain barrier (BBB)
(Neville, Butterworth, James, Hammon, & Stump, 2001; Schwinn, Mackensen, & Brown,
29
2012). The risk can potentially be mitigated by using a lower-dose TXA dosing regimen
(Schwinn et al., 2012).
Women who experience irregular menstrual bleeding should not take TXA unless the cause
of the irregularity is determined; this is in order to avoid potentially delayed diagnosis of
endometrial cancer, which may cause irregular menstrual bleeding. Women who are taking
combination hormonal contraceptives are at increased risk of a deep-vein thromboembolism
and arterial thromboses, and should therefore only take TXA if there is a strong medical
need, as the addition of TXA treatment can theoretically heighten the risk of a thrombotic
event. Further, women who are pregnant or planning to become pregnant should not take
TXA unless it is strongly indicated, as TXA crosses over to and may affect the fetus. TXA
passes into the breastmilk, and therefore because of the unknown effects of TXA on the
fetus, warning should be given to women who are breastfeeding. Consideration should also
be taken when treating men who may father a child, as TXA passes into the semen, inhibiting
its fibrinolytic activity (Liedholm, 1973).
Due to the excretion of TXA by glomerular filtration, TXA may accumulate in patients with
renal insufficiency. According to the product monograph, the recommended dose reduction
for renal failure is: 15 mg orally per kg body weight, twice daily, in patients with serum
creatine concentrations of 120 to 250 μmol/L; 15 mg orally per kg body weight every 24-
hours in patients with serum creatine levels of 250 to 500 μmol/L, and 15 mg orally per kg
body weight every 48-hours at serum creatine levels of 500 μmol/L or more. Precautions
should be taken when treating patients who experience hematuria from the upper urinary
tract. When prescribing TXA, warning should also be given to patients who are obese or
diabetic, have polycystic ovarian syndrome or a history of endometrial cancer, or women
already being treated with estrogen or tamoxifen.
30
1.5.6 DRUG INTERACTIONS
TXA should be taken with caution and close physician supervision if procoagulants (e.g.,
prothrombin complex concentrates, recombinant factor VIIa) are co-administered. Potential
theoretical drug-drug interactions may lead to myocardial infarction if TXA is co-
administered with hormonal contraceptives, hydrochlorothiazide, desmopressin, sulbactam or
ampicillin, carbazochrome, ranitidine, nitroglycerin, and combination hormonal
contraceptives, according to the product monograph.
1.5.7 SIDE EFFECTS AND ADVERSE EVENTS
Potential side effects of TXA administration may include allergic reaction, obstruction of the
central retinal artery or vein, sudden or unexpected visual disturbances, hypotension, cerebral
infarction or thrombosis, myocardial infarction, deep vein thrombosis or arterial thrombotic
event, and acute renal cortical necrosis leading to unusual bladder or kidney function. TXA
may cause dizziness, and may therefore impair one’s ability to drive or operate heavy
machinery. Seizures are the only truly established serious adverse event (Keyl et al., 2010; Z.
Lin & Xiaoyi, 2016).
Adverse events include nausea, vomiting, diarrhea, allergic contact dermatitis, persistent
dizziness and hypotension, and retinal changes. Rare case adverse events include acute
myocardial infarction, venous or arterial thrombosis, cerebrovascular accident, cerebral
thrombosis, acute renal cortical necrosis, central retinal artery or vein obstruction, impaired
colour vision, visual acuity, or blurred vision, dizziness, and seizure (Std, n.d.).
1.6 DOSING REGIMENS IN TRANEXAMIC ACID TREATMENT
The ideal dosing regimens for TXA in various clinical indications are not well-defined, and
the doses used in clinical studies vary. The recommended dose of 500mg TXA oral tablets
31
for conization of the cervix, epistaxis, and hyphaema is 2-3 tablets every 8-12 hours for 12
days, 10 days, and 7 days, respectively. For menorrhagia, 2-3 tablets should be taken 3-4
times daily for several days upon the onset of very heavy bleeding. In patients with
coagulopathies who are undergoing dental surgery, it is recommended that an oral TXA
should be given at a dose of 25 mg per kilogram of bodyweight 2 hours before dental
surgery, in addition to factor replacement. Post-operatively, oral TXA should be given at a
dose of 25 mg/kg 3-4 times daily for 6-8 days. To treat hereditary angioneurotic oedema,
patients may benefit from intermittent or continuous treatment with 2-3 tablets, 2-3 times
daily for several days. Dose adjustment should be made for patients with impaired renal
function. Patients with serum creatinine concentrations of 120 to 250 μmol/L should be
administered 15 mg orally tranexamic acid per kg body weight, twice daily. At serum
creatinine levels of 250 to 500 μmol/L, the dosage should be 15 mg orally per kg body
weight at 24-hourly intervals. At serum creatinine levels of 500 μmol/L or more, 15 mg
orally per kg body weight should be given at intervals of 48 hours between doses.
In Japan, the recommended usual daily adult dosage for oral is 750–2000 mg, divided into
three or four doses (McCormack, 2012). Thus, doses up to 1500 mg daily, divided into
several administrations, appear to be safe and well tolerated by patients of various clinical
conditions.
1.7 TRANEXAMIC ACID TREATMENT IN TRAUMA AND NEUROSURGICAL
CONDITIONS
Several studies have evaluated the use of TXA in trauma, surgery, and various neurosurgical
conditions. A large, randomized controlled trial investigated the efficacy of early TXA
administration in trauma patients who were experiencing or at risk for significant
hemorrhage. Patients were administered an intravenous loading dose of 1000 mg TXA – or
matching placebo – over 10 minutes, followed by a 1000 mg maintenance dose over 8 hours.
The results showed that TXA significantly reduced all-cause mortality at 4 weeks as well as
the rate of death due to bleeding (CRASH-2 trial collaborators et al., 2010). A sub-study of
this trial in a cohort of patients with traumatic intracranial hemorrhage saw no statistically
32
significant difference in hemorrhage growth in TXA-treated compared to control subjects
(CRASH-2 Collaborators, Intracranial Bleeding Study, 2011).
There have been inconsistent results from studies assessing the efficacy of TXA in reducing
re-bleeding in subarachnoid hemorrhage patients.
In a large, randomized, placebo-controlled trial, patients with subarachnoid hemorrhage were
administered 4–6 g/day of TXA, or placebo, for up to 4 weeks. There was a significant
reduction in the incidence of re-bleeding in TXA-treated patients compared to controls. It is
however important to note that they saw no between-group difference in outcome at 3-
months because of a concurrent increase in ischemic complications in the TXA group
compared with placebo (Vermeulen et al., 1984).
A recently published retrospective study assessed the efficacy of oral 650 mg twice a day
TXA in treating residual CSDH (Tanweer et al., 2016). Fourteen patients with 20 CSDHs
were included. They reported 91.3% reduction in residual hematoma size after TXA therapy.
This study, however, had several limitations. First, and most significantly, it was not a
randomized, controlled trial. There was no concurrent or historical control group, and it
cannot be concluded that TXA was efficacious without comparison to a control group of
CSDH patients. Second, TXA was started after initial treatment with bedside twist-drill
hematoma evacuation and subdural evacuating portal system (SEPS). However, there were
no AEs or SAEs associated with the medication reported in any of the study patients,
supporting the safety of TXA in patients with residual CSDH.
There is currently a phase 2, double-blind, placebo controlled, randomized, parallel-design
study underway assessing tranexamic acid in chronic subdural hematoma (TRACS) (Iorio-
Morin, Blanchard, Richer, & Mathieu, 2016) (ClinicalTrials.gov Identifier: NCT02568124).
This multi-center Canadian trial is assessing the efficacy of TXA in faster resolution of
CSDH in non-surgical patients after conservative management. They plan to recruit 130
patients to be randomly assigned to either the TXA arm or the control arm. The TXA arm
will receive one 750mg dose of TXA daily, while the control group will receive one placebo
33
tablet daily for 20 weeks, at which point they will determine CSDH volume as a measure of
CSDH resolution (their primary outcome measure).
34
2. STUDY RATIONALE
As our population continues to age at an unprecedented rate (Bélanger A, Martel L, &
Caron-Malenfant E, 2005), by 2030 the prevalence of CSDH is expected to surpass that of
brain tumours becoming the most common condition requiring neurosurgery (Balser, Farooq,
Mehmood, Reyes, & Samadani, 2015). With surgery as the only current treatment for CSDH
(Santarius et al., 2009), a low-risk alternative for this sentinel event is strongly desired.
We hypothesize that tranexamic acid treatment can prevent the enlargement of residual
CSDH after surgery, or prevent re-bleeding that may require repeated surgical intervention.
However, no studies to date have prospectively examined whether TXA is effective in
improving the clinical course of residual CSDH after surgical drainage. As described above,
there is currently a multi-center trial (TRACS) for TXA efficacy primarily in non-surgical
CSDH (Iorio-Morin et al., 2016). As of yet, there is no data published from this study.
Therefore, there is still no completed study providing compelling support in favor of TXA as
an efficacious non-surgical intervention in CSDH volume resolution. Moreover, the TRACS
study is recruiting mainly conservatively-managed, non-surgical patients, rather than
primarily investigating the efficacy of TXA in preventing post-operative recurrence. Second,
it is possible that the TXA half-life period is too short to be given only once a day, as is
currently outlined in their protocol.
To verify the potentially therapeutic effects of TXA in CSDH, a randomized controlled trial
would be required to examine its efficacy compared to current medical practice. We therefore
designed the present pilot study to investigate the feasibility of conducting a trial investigating
TXA treatment success in post-surgical, residual chronic subdural hematomas. Our primary
objective of this pilot is to evaluate the feasibility of conducting this trial at St. Michael’s
Hospital. Secondarily, we will be evaluating the efficacy if TXA in preventing post-operative
residual subdural hematoma growth, as well as TXA safety in this study population.
There is also a lack of literature regarding the course of volume changes in CSDH and in
residual hematomas after burr-hole surgery. Our study will facilitate a close patient
35
observation in the beginning of the treatment course and generate source data on the volume
courses of postoperative CSDH and consequently the development of recurrent CSDH.
Our present pilot study is also designed to obtain preliminary data for a future multicenter,
double-blinded, randomized, placebo-controlled in post-operative patients.
Should this larger study demonstrate TXA efficacy in residual CSDH treatment, it could be
implemented as a safe alternative to repeat surgery, lowering repeat-surgery rates, and
sparing patients physical and emotional stress. The high affordability of oral TXA therapy
would also benefit the healthcare system. The mean cost per SDH patient, attributed to
operating time alone, was estimated at $7,588 for burr-holes procedures and $10,416 for
craniotomy procedures (Regan, Worley, Shelburne, Pullarkat, & Watson, 2015). These
estimates did not include other inpatient hospital costs. Further, the national annual cost of
subdural hematomas in the United States has been estimated to be $1.6 billion as of 2007,
and rising with increasing incidence (Frontera, Egorova, & Moskowitz, 2011). In
comparison, 500mg TXA oral tablets cost approximately $140 for 100 tablets. The economic
value of being able to treat CSDH with TXA rather than surgery would not be insignificant.
36
2.1 STUDY DESCRIPTION AND OBJECTIVES
2.1.1 PRIMARY STUDY OBJECTIVE
2.1.1.1 Feasibility
As a pilot study, our primary study objective was to gather preliminary study feasibility data,
and data on the course of hematoma volume changes under current treatment practice. This
would inform the conduct of a future multi-center, double-blind randomized controlled trial
assessing TXA efficacy in post-surgical patients.
Our outcome measures for this objective were participant recruitment and attrition rates
over the study duration, participant eligibility rates, study drug compliance, and
outcome measure completion.
2.1.2 SECONDARY STUDY OBJECTIVES
2.1.2.1 Hematoma volume change
As a secondary study objective, we sought to determine the efficacy of TXA treatment in
residual CSDH after burr-hole surgery.
Our primary outcome measure was defined as the hematoma-volume reduction (or
growth) as a percent change from pre-operative scan to follow-up scan after 4-8 weeks
of TXA therapy. These volumes were calculated by an observer-blinded analysis of the
CT scans.
37
Secondary outcome measures were the rate of reoperation, the time to reoperation
during the study course due to hematoma recurrence, and the number of patients with
resolution of the CSDH after 4-8 weeks and 8-12 weeks.
2.1.2.2 Neurological status
As another secondary study objective, we assessed neurological status at baseline and follow-
up.
Neurological outcome was assessed on the following scales: National Institutes of
Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Glasgow Coma Scale
(GCS), Markwalder Grading Score (MGS), and the Glasgow Outcome Scale-Extended
(GOSE).
2.1.2.3 Quality of life
As another secondary study objective, we also assessed patient quality of life (QOL).
Our outcome measures for this objective were scores on the 36-item Short Form health
survey (SF-36) (Brazier et al., 1992) and the Health Utilities Index (HUI®) (Horsman,
Furlong, Feeny, & Torrance, 2003a), two validated tools for health-related QOL
assessment.
2.1.2.4 TXA safety
Our final secondary study objective was to monitor drug safety and safety of our chosen TXA
dose regimen.
Our outcome measures for this objective were monitoring regular monitoring of patient
blood counts, urinalyses, and the occurrence of any adverse events (AE), serious
38
adverse events (SAE), and adverse drug reactions (ADRs) during the study course,
particularly thromboembolic events.
2.2 STUDY DESIGN
TRACE was designed as a single-centre, open-label randomized controlled trial. Study
participants were randomized to one of two treatment arms: the control arm, which received
standard postoperative treatment, and the treatment arm, which received standard
postoperative treatment in addition to daily oral tranexamic acid.
2.2.1 STUDY DURATION AND TIMELINE
Participants were enrolled in the study for up to 8-12 weeks, or until the time of their last
clinical follow-up in the neurosurgery clinic. We followed-up with participants at in-hospital
visits, as well as by telephone between the in-hospital visits. The timeline and follow-up
schedule are presented below in Figure 6.
Outpatient follow-ups were scheduled to coincide with standard neurosurgical clinic follow-
ups following surgery for CSDH. Clinically, the first neurosurgical follow-up is typically
scheduled between 4-8 weeks after burr-hole drainage. Therefore, the first of two outpatient
follow-up study visits were scheduled at 4-8 weeks after surgery, to align with neurosurgical
follow-up. While some patients return to clinic at first follow-up with complete hematoma
resolution, many still have residual CSDH. Patients with residual CSDH for whom a second
neurosurgical follow-up is clinically required are typically seen approximately one month after
their first follow-up visit. Therefore, the second in-hospital study follow-up was scheduled for
8-12 weeks, after which the study was completed and patients discontinued the study
medication.
39
Two telephone interviews were also scheduled as part of study follow-up to monitor TXA
safety as part of the secondary study outcome. With the phone calls, we evaluated participants
for concomitant medications, co-morbidities, study medication compliance, AEs or SAEs, and
ADRs.
The first telephone interview was conducted by research personnel 2-3 weeks after study
enrollment. The second telephone interview was scheduled approximately 2-3 weeks after the
first in-hospital visit. Patients typically spend less than one week in hospital after surgical
CSDH evacuation. If, however, the patient was still an in-patient at the scheduled time for the
2-3-week telephone interview, the interview was conducted in person by research personnel.
If participants were discharged from neurosurgical care at the first clinic follow-up, we
determined that they reached a study endpoint, and TXA was discontinued. If the participant
was scheduled to be seen again at a second clinic follow-up at 8-12 weeks, they continued
taking the TXA until the second visit, at which time the TXA or placebo was discontinued.
Participant consent was reconfirmed at each study visit and telephone call.
Figure 6. Timeline of study follow-up visits and phone calls. The overall study duration is up to 8-12 weeks, consisting of two in-hospital study visits and two telephone calls.
Study week 0 (Baseline
visit): Day of randomization
Study week 2-3: First
telephone follow-up
Study week 4-8: First in-hospital
follow-up visit at clinic
Week 2-3 after first visit: Second telephone follow-
up
Study week 8-12: Final in-
hospital follow-up visit at clinic
40
Study variables collected at each in-hospital and telephone follow-up are presented in Table 1. Table 1. Variables collected at each in-hospital and telephone follow-up for study duration
41
2.2.2 RESEARCH ETHICS BOARD AND HEALTH CANADA APPROVAL
Prior to trial initiation, institutional Research Ethics Board (REB) and Health Canada
approval were obtained. Our institutional REB also approved all study documents, including
the study protocol, case report forms (CRFs), participant informed consent forms,
recruitment scripts, and any study information given to patients. All pertinent staff were
trained in the study protocol and related study procedures, including all co-investigators,
neurosurgeons and neurosurgery residents, all involved registered nurses, nurse practitioners,
hospital pharmacists, and research pharmacists.
In accordance with Health Canada recommendations, the trial was registered at
ClinicalTrials.gov, a public clinical trial registry (ClinicalTrials.gov Identifier:
NCT03280212).
2.3 PARTICIPANT ELIGIBILITY
All patients admitted to St. Michael’s Hospital with radiologically-confirmed diagnosis of
chronic subdural hematoma were screened for study eligibility. We defined chronic subdural
hematoma as any subdural collection of liquefied or partially-liquefied blood, including
subacute and acute-on-chronic subdural hematomas.
2.3.1 INCLUSION CRITERIA
In order to be eligible for study participation, patients must have met the following criteria:
• been diagnosed with chronic subdural hematoma, and undergone unilateral or
bilateral burr-hole craniostomy or mini-craniotomy for hematoma evacuation;
• been above the age of 18;
42
• demonstrated competence to take study medication properly and regularly, or had
access to a caregiver that was able to comply with accurate study medication
administration
There were several reasons CSDH patients presenting to our institution were discharged
without neurosurgical intervention, including: mild symptoms that the primary neurosurgeon
felt did not require immediate surgical intervention; very small hematoma size that the
primary neurosurgeon felt would resolve on its own; or poor surgical candidacy, particularly
resulting from advanced cardiovascular comorbidities, advanced age, or multimorbid status.
2.3.2 EXCLUSION CRITERIA A comprehensive list of exclusion criteria was developed in light of contraindications and
warnings of TXA administration. Therefore, CSDH patients who met any of the following
criteria were deemed ineligible for study participation:
• Hypersensitivity to TXA or any of the ingredients
• Pregnancy
• Irregular menstrual bleeding with unidentified cause
• Newly-acquired colour vision disturbances
• Acute and chronic renal insufficiency, indicated by a glomerular filtration rate (GFR)
≤ 30 mL/min
• Hematuria, caused by diseases of renal parenchyma
• Current alcohol or drug abuse, or recreational drug use
• Concomitant intake of hormonal contraceptives, factor IX complex concentrates
prothrombin complex concentrate (PCC), and anti-inhibitor coagulant concentrates
(recombinant activated factor VII, activated factor IX complex, factor eight inhibitor
bypassing activity (FEIBA))
• Active, history, or increased risk (as defined by the attending physician) of
thrombotic events (including deep vein thrombosis, pulmonary embolism, cerebral
43
venous thrombosis, arterial thrombotic events), symptomatic carotid stenosis,
myocardial infarction, acute coronary syndrome, coronary artery disease, or
consumption coagulopathy within the past 2 years
• History of angioplasty with cardiac stent placement or mechanical heart valve
• Active or history of brain pathologies such as stroke (hemorrhagic and ischemic),
subarachnoid hemorrhage, or malignant brain tumors (glioma, metastasis and others)
as well as history of seizures within the past 2 years
• Contraindication to stopping full therapeutic doses of non-ASA antiplatelets,
warfarin, rivaroxaban, apixaban, dabigatran, or other anticoagulant for 2 weeks after
surgery
• Patients requiring immediate revision surgery (as defined by attending surgeon)
• Inability of oral drug intake or missing support to guarantee oral drug intake
2.3.3 PATIENT SCREENING AND DETERMINING PATIENT ELIGIBILITY
We screened all consecutive patients admitted to St. Michael’s Hospital with radiologically-
confirmed diagnosis of chronic subdural hematoma. We screened the patients’ medical charts
to determined their eligibility for study participation in light of the aforementioned eligibility
criteria. After initial screening, patient eligibility was discussed with and confirmed by the
principal investigator or a study co-investigator.
2.3.4 PARTICIPANT RECRUITMENT
Patient recruitment took place from the Neurosurgical Program at St. Michael’s Hospital.
Participants were primarily recruited from the Neurosurgery Ward, and in some instances from
the Emergency Department.
The study was introduced to each patient by a member of his or her circle of care, either a
physician, registered nurse, or nurse practitioner. We then explained the study in full detail to
44
eligible patients with unilateral or bilateral CSDH who were planned to or had undergone
surgery. We obtained written informed consent from patients who agreed to study
participation, or, the event where the patient could not provide informed consent due to
impaired neurological status, we obtained informed consent from the patients substitute
decision maker (SDM) or power of attorney (POA). If a patient refused to participate in the
study, we documented the reason for non-enrollment in the screening log.
2.3.5 PARTICIPANT RANDOMIZATION
Randomization was performed only after we obtained informed and written consent, and was
done so within 24 hours of obtaining consent. The randomization sequence was developed
independently by a statistician and clinical trials methodologist, prior to trial initiation.
Randomization was performed by trained technicians and pharmacists in the St. Michael’s
Hospital Research Pharmacy so that we remained blinded to the randomization sequence to
ensure allocation concealment. A computer-generated randomization sequence was developed
by the study statistician prior to study initiation, and this sequence was followed by the
Research Pharmacy for each patient enrolled to the trial.
2.4 STUDY DRUG
2.4.1 TXA DOSING REGIMEN
The TXA dosage regimen we determined for our trial was informed by previously detailed
data on pharmacokinetic as well as pharmacodynamic properties. We focused specifically on
assessing patient safety of the drug dose in particular.
On the basis of the current available data presented in our literature review, we decided to
investigate a post-operative dose regimen as follows: Patients of the TXA arm were given 500
mg TXA orally, 3 times a day (TID). Participants of the comparative control arm did not
receive any additional tablets.
45
The TXA dosage was conceptualized for the majority of patients with a body weight between
60 to 100 kg. Weight deviation from this were considered with a dose adjustment of 1000 mg
TXA two times a day (BID) for a body weight above 100 kg, and 500 mg TXA BID for body
weight below 60 kg. This regimen was selected, because the body weight of an average
Canadian is 80.7 kg and the maximum daily dosage of the present trial intended to be below
the dose recommendation according to the TXA product monograph (25 mg/kg) to avoid long
term toxicity. Dosage adjustment due to renal insufficiency was not required as patients with
acute and chronic renal insufficiency indicated by a GFR ≤ 30 mL/min were not deemed
eligible.
A logistical factor in our dose regimen selection was the availability of oral TXA in Canada,
where it is available in 500 mg tablets. Although TXA tablets are divisible, requiring patients
to divide their tablets could lead to improper drug intake or noncompliance, and was therefore
avoided. To mitigate these potential concerns, a three times-per-day dosage regimen was
proposed. The oral route for drug administration was chosen to enhance patient compliance
and minimize study withdrawals due to discomfort from intravenous administration. TXA
cannot be crushed for administration as this would alter pharmacologic properties.
Patients randomized to the TXA arm were started on the study drug within two days of surgery.
Concomitant medications were continued throughout the study course.
The inpatient dosing schedule is presented in Table 2.
Table 2. TXA dose administration schedule according to bodyweight Time of dose administration Bodyweight range 0830 1230 1630 60-100kg 1x 500mg tablet 1x 500mg tablet 1x 500mg tablet <60kg 1x 500mg tablet None 1x 500mg tablet >100kg 2x 500mg tablet None 2x 500mg tablet
Upon discharge, patients were advised to take the study drug as close to the inpatient dosing
schedule as possible, depending on their specific dosing regimen.
46
2.4.2 TXA DISPENSING PROCEDURES
TXA was stored in and dispensed by the Research Pharmacy under temperature-regulated
conditions, in accordance with Health Canada regulations.
TXA was first dispensed as an in-patient supply to be administered to the patient by their
registered nurse. The in-patient supply was dispensed in vials containing a day’s dose of
tablets, corresponding to the appropriate weight-adjusted dosing regimen. This in-patient
supply was stored in a locked, temperature-regulated medication box on the Neurosurgery
ward in the medication room.
At the time of discharge, an out-patient supply of two 100-tablet bottles was dispensed for
them to self-administer the tablets at home. A surplus of tablets was provided to ensure the
patients had enough to complete the study. At this time patients were also discharged with a
Discharge Information Package detailing proper study drug storage and administration.
2.4.3 MONITORING STUDY DRUG COMPLIANCE Study drug compliance was monitored by having participants log TXA intake in a study ‘Drug
Diary’. There, patients documented the time each of their doses was taken, as well as any
missed or forgotten doses.
Upon study completion, patients returned any remaining study drug tablets to the Research
Pharmacy.
47
3. STUDY METHODS
3.1 DATA COLLECTION
3.1.1 STUDY FEASIBILITY DATA
Reasons for ineligibility were collected and documented in the participant screening log.
Likewise, reasons for non-recruitment were collected and documented. Similarly, the number
of study withdrawals, time of study discontinuation after study onset, as well as reasons for
study discontinuation, were recorded.
3.1.2 RADIOLOGIC DATA The CT imaging department at St. Michael’s Hospital was notified immediately of the patients
enrolled in the trial to ensure all study patients were imaged using the GE Revolution CT
Scanner for consistency.
3.1.2.1 Hematoma volume calculation
Subdural hematoma volumes are typically not measured for clinical purposes, and therefore a
standard 3D volume-rendering software for these hemorrhages was not in use for clinical
purposes. The measurements collected for clinical purposes most often include the maximum
thickness of the hematoma, and occasionally the maximum anterior-posterior dimension.
Intracranial hematomas have been measured using a validated ABC/2 method (Kothari et al.,
1996; Kwak, Kadoya, & Suzuki, n.d.). This equation is a simplification of the equation for
calculating an ellipsoid volume. The measurement is calculated in the axial imaging plane as
follows: A represents the maximum diameter of the hemorrhage; B represents the maximum
48
width, taken at 90 to A; and C represents the number of axial CT thin-slices on which
hemorrhage is appreciable, times the thickness of the CT slice.
This method is efficient and accurately generates a volume estimate for an ellipsoid-shaped
hemorrhage. Based on mathematical derivation, some have shown that the ABC/2 method
can be accurately applied to SDH volume estimation (Gebel et al., 1998; Kasner, 1999; Sucu,
Gokmen, & Gelal, 2005). Sucu et al. (2005) assessed the validity of the ABC/2 method for
measuring typically crescent-shaped subdural hematomas in comparison to the ‘gold
standard’ of computer-assisted 3D-volumetric analysis, and found that, based on
mathematical theory and derivation, the volume estimates were sufficiently accurate.
However, an inherent limitation of this method is that it assumes the lesion has an ellipsoid
morphology, and overestimates the volume of more irregular shapes. Therefore, the greater
the lesion’s deviation from an ellipsoid geometry, the less accurate the volume estimate.
Several more recent studies using ABC/2 method to calculate actual CSDH found it
inaccurate, concluding that the imprecision of this mathematical estimation would be
insufficient for a clinical trial in which even small SDH volume differences can be clinically
significant (Manickam, Marshman, & Johnston, 2016). Further, Stanisic et al. (2014) showed
that using radiologic features such as maximum thickness and anterior-posterior dimension
to estimate SDH size is also inaccurate (Stanišić, Groote, Hald, & Pripp, 2014).
The Carestream PACS medical imaging viewing software available at our institution has a
semi-automated lesion measurement tool which allows the viewer to delineate the borders of
lesion, with the aid of computer-recognition software that guides the demarcation. The
computer system subsequently generates a 3-Dimensional lesion volume by estimating the
overall shape of the lesion based on the 2-Dimensional tracings made at each slice. This tool
is fairly accurate in clinical use for measuring the volumes of tumors or hematomas, as well
as liver and lung lesions for which the PACS system has predefined measurement algorithms
based on the generally predictable shape of these lesions. However, the tool is not as accurate
in predicting the 3-Dimensional shape of a subdural hematoma, as it generates too uniform a
shape, typically omitting the hematoma fluid at its boundaries that only appears as a thin strip
49
on some CT slices. Furthermore, this tool is only functional on CT scans produced with 2.5
mm slices or smaller, such as those used for scans for preoperative planning taken with the
GE Revolution scanner.
In light of these volume measurement techniques and their limitations, in order to produce
the most accurate estimate of hematoma volume, we employed the ‘gold standard’
measurement technique. This approach begins with manually delineating the area of the
hematoma on each axial thin slice of the CT scan. Each of these areas is then multiplied by
the thickness of the CT slice (depending on the CT scanner used, the thickness was either
1.25 mm, 1.63 mm, 2.5 mm or 5 mm, though 2.5 mm and 5 mm are most common) to
produce a volume, and these volumes were added together to produce an estimate of the
entire hematoma volume (Figure 7). We carried out these volume measures for each of the
available pre-operative, immediate post-operative, and follow-up CT scans for all study
participants. The change in hematoma volume was reported as a percent resolution or
growth, calculated by dividing the hematoma volume at 4-8 weeks by the preoperative
volume, and multiplying by 100 to yield a percentage.
50
A
B
C
51
Figure 7. Hematoma tracing technique and measurement of other radiologic features using the Carestream PACS viewer. In order to calculate the hematoma volume using the gold standard method, the area of the hematoma is manually delineated on each CT thin slice where the hematoma is visible in the axial view, as shown in this figure (A, B, C). Each area is multiplied by the thickness of the CT thin-slices (for this CT, 0.125 cm), and the areas are summed to yield a cumulative hematoma volume. The measurement of radiologic features including midline shift (A), maximum hematoma thickness (B), and maximum anterior-posterior dimension (B), are also shown here.
3.1.2.2 Other radiologic features
All other radiologic hematoma features were collected on the axial-view, preoperative CT
scans. Other radiologic variables collected were those related to mass-effects of the SDH,
and included: presence of midline shift, direction of midline shift (left to right, or right to
left), sulcal effacement, subfalcine herniation, brainstem compression, cisternal compression,
ventricular compression, and hydrocephalus. The size of midline shift was measured by first
drawing a line connecting the anterior and posterior insertions of the falx cerebri, and
drawing a second perpendicular line measuring the distance from this line to the septum
pellucidum (Stanišić et al., 2013a).
C
52
Other radiologic variables collected with respect to the hematoma were: hematoma laterality
(left, right, or bilateral), hematoma location (frontal, parietal, temporal, or occipital),
hematoma density (heterogenous or homogenous; hyperdense, isodense, or hypodense),
presence of septations or loculations, presence of a fluid-fluid level, presence of an
appreciable hematoma membrane, maximum hematoma thickness and maximum anterior-
posterior dimension. When reporting the maximum anterior-posterior dimension for bilateral
subdural hematomas, the largest maximum dimension was used. When reporting the
maximum hematoma thickness of bilateral hematomas, the thicknesses of each of the
hematomas was summed to for a cumulative maximum thickness.
We also sub-classified the study participants’ subdural hematoma types according to the
grading scale developed by Alves et al. (2016), which is described in Table 4 (Alves,
Santiago, Costa, & Pinto, 2016).
Table 3. Subdural hematoma radiologic sub-classification system*
Type Imaging Setting I Hyperdense relative to brain, relatively
homogeneous Acute
II Isodense relative to brain, relatively homogeneous
Subacute
III Hypodense retlative to brain, relatively homogeneous
Chronic
IV Isodense to hypodense, relatively heterogeneous Evidence of recent rebleeding V Hypodense in its liquefied component,
relatively heterogeneous; internal septations and loculations
Chronic
VI Calcified hyperdense, relatively homogeneous Chronic
*Alves et al. (2016) For each study patient, the hematoma volumes and these radiologic variables were collected
for preoperative, immediate post-operative, first follow-up, and second follow-up CT scans.
53
3.1.3 NEUROLOGICAL TESTS AND ASSESSMENTS
As indicated in Table 2, we performed all neurological tests and evaluations at baseline, at
the first in-hospital study visit, and the second in-hospital study visit, where applicable.
Details of each grading scale are provided as appendices.
3.1.3.1 Glasgow Coma Scale
The Glasgow Coma Scale (GCS) is a universal neurological scale that uses defined stimuli to
assess for impaired consciousness (Teasdale & Jennett, 1974). It is used for its objective
assessment of impaired consciousness. Individuals are assessed and graded on three response
elements: eye response, verbal response, and motor response, each with a minimum possible
grade of 1, and maximum possible grades of 4, 5 and 6, respectively. Lower grades indicate
severely impaired responding. Grades from each response are then summed to yield a
cumulative score, where the maximum achievable score is 15, meaning full consciousness,
and the minimum achievable score is 3, indicating the lowest level of conscious awareness
(Appendix A).
3.1.3.2 Glasgow Outcome Scale-Extended
The Glasgow Outcome Scale-Extended (GOSE) is a widely-used neurological scale for
assessing functional outcome (Jennett, Snoek, Bond, & Brooks, 1981; Weir et al., 2012). The
GOSE is measured on an ordinal scale with five categories: Death, Vegetative State, Severe
Disability, Moderate Disability, and Good Recovery. The categories of Severe Disability,
Moderate Disability, and Good Recovery category are each subsequently split into upper and
lower levels yielding a total of eight categories, in order to increase the scale’s sensitivity in
detecting clinically-significant treatment effects (Appendix B).
54
3.1.3.3 Markwalder Grading Score
The Markwalder Grading Score (MGS) is a scale that was developed for assessing the
neurological status of patients with chronic subdural hematomas (Markwalder, Steinsiepe,
Rohner, Reichenbach, & Markwalder, 1981). The scale ranges from 0 to 4, with 0 indicating
the patient has normal neurological status and no symptoms, and 4 indicating the patient is
comatose and non-responsive to stimuli (Appendix C).
3.1.3.4 modified Rankin Scale
The modified Rankin Scale (mRS) is a neurological scale that measures degree of disability
and dependency, most commonly used for patients who have suffered a stroke or other
neurological trauma or disability (Bonita & Beaglehole, 1988; Rankin, 1957a, 1957b;
RANKIN, 1957). It is scored on a scale from 0 to 6, with 0 meaning no symptoms and
perfect health, and 6 meaning death. A median score of 3 indicates moderate disability,
requiring some help, but able to walk without assistance, while a score of 4 indicates not
being able to walk without assistance and 5 meaning the patient is bedridden (Appendix D).
3.1.3.5 National Institutes of Health Stroke Scale
The National Institutes of Health Stroke Scale (NIHSS) is a comprehensive tool used to
assess the neurological disability caused by a stroke (Brott et al., 1989). We administered the
NIHSS because it allows for an objective assessment of several functional modalities. It was
designed for use in clinical trial settings, and is widely used by investigators in stroke trials.
It is composed of 11 assessments, which examine degree of impairment with respect to 11
functional capacities: level of consciousness, horizontal eye movement, visual fields, facial
palsy, arm mobility, leg mobility, limb ataxia, sensory capacity, language, speech, and
extinction and inattention. The lowest possible score on each section is 0, indicating normal
function in that specific capacity, and higher scores indicating increasingly severe
55
impairment in that capacity. The scores on each assessment are totaled, yielding a total
possible overall NIHSS score from 0 to 42.
3.1.4 QUALITY OF LIFE (QOL) MEASURES
The RAND 36-Item Short Form Health Survey 1.0 (SF-36) (Brazier et al., 1992) and Health
Utilities Index (HUI®) (Horsman et al., 2003a) were administered at baseline, at first follow-
up, and at final follow-up, as measures of mental, physical, and health-related quality of life
(QOL) and health-related (QOL). Participants completed the questionnaires on their own,
with the help of a family member if they were unable to circle the answers. Regardless, the
patients were encouraged to answer the questions honestly and for themselves.
3.1.4.1 SF-36
3.1.4.1.1 SF-36 questionnaire overview
The RAND 36-Item Short Form Health Survey 1.0 (SF-36) is a validated questionnaire that
is used as a subjective measure of quality of life (J. E. Ware & Sherbourne, 1992; J. Ware,
Kosinski, & Keller, 1994). The questionnaire is self-administered, and is often chosen in
clinical research for its timely and straightforward completion, as well as its comprehensive
assessment of a variety of health categories.
Composed of 36 questions, the questionnaire assesses health over eight categories: physical
functioning, bodily pain, role limitations due to physical health problems, role limitations
due to personal problems, role limitations due to emotional problems, emotional well-being,
social functioning, energy and fatigue, and overall perception of one’s own general health.
56
3.1.4.1.2 Scoring of the SF-36
The responses to each of the 36 questions are converted to scores on a scale of 0 to 100, with
scores closer to 0 indicating a poorer health state, and scores closer to 100 indicating a more
favorable health state. The scores on certain preset questions are averaged to yield an overall
score for each of the eight health categories assessed by the questionnaire. The mean (STD)
scores for health controls on each category have been reported as: 70.61 (27.42) for physical
functioning; 52.97 (40.78) for role limitations due to physical health; 65.78 (40.71) for role
limitations due to emotional health; 52.15 (22.39) for energy and fatigue; 70.38 (21.97) for
emotional well-being; 78.77 (25.43) for social functioning; 70.77 (25.46) for pain; and 56.99
(21.11) for general health.
3.1.4.2 HUI
3.1.4.2.1 HUI questionnaire overview
All necessary permissions for use of the Health Utilities Index (HUI) questionnaire were
obtained prior to beginning any study activities.
The HUI is a 15-item questionnaire assessing health-related quality of life (HRQL) (Furlong,
Feeny, Torrance, & Barr, 2001; Grootendorst, Feeny, & Furlong, 2000; Horsman et al.,
2003a; Horsman, Furlong, Feeny, & Torrance, 2003b). It has been validated by several
studies and favored for its sensitivity (Kaplan & Haenlein, 2010). The questionnaire was
designed to be minimally intensive for health subjects to complete, while obtaining the
maximum amount of information needed to classify an individual's health status according to
two classification systems: the Health Utilities Index Mark 3 (HUI3) and Health Utilities
Index Mark 2 (HUI2). The questionnaire asks respondents to focus on their usual or current
health within a specified health status assessment period. The questionnaire used in this study
focused on a specified health status assessment period of the previous one week.
57
The questionnaire is suitable for use among individuals who are experiencing cognition or
attention deficits such as neurosurgery patients, as it can be completed by either the subject
or a respondent other than the subject including a substitute decision maker or other family
member that may act as a proxy on behalf of the respondent. In our study, patients who were
unable to complete the questionnaire on their own were typically those who were consented
to the study by a Substitute Decision Maker (SDM). In those situations, the SDM was the
respondent who completed the HUI questionnaire. Further, not all patients enrolled to the
study spoke fluent English. Because the questionnaire was only available to us in the English
language, the questions were translated to the patient in the dominant language and the
questionnaire was completed by the patient.
The HUI3 and HUI2 health status classification systems are considered to be complementary
to one another. Each scale measures the individual functionality of specified health attributes.
The eight health attributes evaluated by the HUI3 classification system are: vision, hearing,
speech, ambulation, dexterity, emotion, cognition, and pain. The seven health attributes
evaluated by the HUI2 classification system are: sensation, mobility, emotion, cognition,
self-care, pain and fertility (while not directly asked as a question in the questionnaire,
patients are assumed to have full fertility (a score of 1) unless fertility is being assessed
separately for the purposes of the study in question).
3.1.4.2.2 Scoring of the HUI questionnaire
Responses to the survey questions are converted to health attribute levels using a predefined
scoring system. The answers provided by respondents to the 15 items in the questionnaire are
first converted to attribute scores based on preset algorithms. When scoring the
questionnaire, the health attribute level codes are determined from either a response to a
single pre-specified question, or from combinations of responses from a specified subset of
questions. These converted scores – either individual or combinations of scores – represent
the functional level of a specific health attribute, such as hearing. Scores range from 1 to 6,
with 1 indicating the best possible health state for a given attribute, and higher scores
indicating the poorest possible health state for a given attribute, meaning that the health
58
attribute is at its lowest functional level and the individual is at their most disabled for that
given health attribute. Detailed descriptions of each single-attribute level for the HUI3 and
HUI2 are presented in Appendix E.
The HUI3 and HUI2 single attribute utility scores are subsequently combined to determine
HUI3 and HUI2 overall multi-attribute health-related quality of life (HRQL) utility scores.
These scores range from a value of 0 meaning dead, to 1 meaning perfect health, though
negative values are also permitted. Negative multi-attribute HRQL scores imply a health
state worse than death. Mean population-norm HUI3 and HUI2 multi-attribute HRQL scores
in individuals 65 years old or older have been reported as 0.697 0.016 and 0.798 0.009,
respectively.
These HUI3 and HUI2 multi-attribute scores are also subsequently classified into four
disability categories: none, mild, moderate, and severe.
According to the scoring guideline recommendations, single and multi-attribute HUI3 and
HUI2 scores are presented using conventional summary statistics, as well as with plots of
frequency distributions.
59
3.2 CASE REPORT FORM AND DATA COLLECTION MONITORING
The Case Report Form (CRF) – including all study related medical test results,
questionnaires, and data collection forms – were identified by a unique identification number
assigned to the study participant after receipt of the signed consent form. The hardcopies of
all questionnaires, scoring sheets and medical testing were stored at the Injury Prevention
Research Office in a locked filing cabinet. All results obtained from QOL questionnaires and
study-related medical assessments were filled in the CRF as an encrypted file on a secure St.
Michael’s Hospital Network for analysis. Any and all protocol deviations were documented
in a protocol deviations log, and assessed and signed-off by the study principal investigator.
Necessary steps were taken to mitigate the re-occurrence of any protocol deviations.
60
3.3 SAFETY MONITORING
3.3.1 LABORATORY TESTS
Routine blood tests and urinalyses were performed at baseline, and at both in-hospital study
visits, to assess any changes that could have been associated with TXA administration. Blood
testing was used to monitor for adverse events and included: complete blood count; sodium,
potassium, glucose, and creatinine levels; prothrombin time (PT); International Normalized
Ratio (INR); activated partial thromboplastin time (APTT); and serum pregnancy test, if
applicable. The estimated glomerular filtration rate (eGFR) was calculated using the
validated CKD-EPI online formula (Levey et al., 2009).
3.3.2 OPHTHALMOLOGICAL EVALUATIONS
Due to the possible risk of vision-related adverse events, we asked participants to report any
visual disturbances experienced during the study course during telephone and follow-up
interviews. Ophthalmological examinations were also performed at baseline and both in-
hospital follow-up visits to rule out degenerative changes of the retina.
Fluctuations and deviations from normal values in vital signs, blood chemistry, urinalyses,
and ophthalmological tests were clinically expected. Abnormal results – as determined by the
qualified testing physician, neurosurgeon, ophthalmologist, laboratory or diagnostic
personnel – were noted as clinically significant. If there were significant deviations from
normal levels, they were evaluated by the study principal investigator (PI) to determine
whether they were related to an existing comorbidity or concomitant medication, or whether
they were possibly related to the study drug. Any potential for study discontinuation as a
result of such safety concerns was discussed by the research team and ultimately determined
by the study PI.
61
3.3.3 MONITORING AND MANAGING ADVERSE EVENTS AND ADVERSE
DRUG REACTIONS
Serious adverse events (SAE) as well as adverse events (AE) occurring during the study
schedule were documented throughout the study course. AEs were defined as any
unfavorable event occurring during the study course. All adverse events were assessed and
graded by the principal investigator, and their occurrence led to immediate investigation and
medical treatment, if deemed necessary by the principal investigator and/or most responsible
physician. Any related, possibly related, and unexpected SAEs and AEs were reported to our
institutional REB at St. Michael’s Hospital according to their reporting guidelines. Likewise,
although we did not encounter any serious and unexpected adverse drug reactions (ADRs),
they would have been documented and reported to Health Canada in accordance with
regulations. Any serious ADRs would have resulted in immediate study discontinuation.
3.4 STUDY ENDPOINTS, PARTICIPANT DISCONTINUATION, AND
PARTICIPANT WITHDRAWAL
The occurrence of thrombotic events (including transient ischemic attack), allergic reaction
to TXA, and colour vision disturbances were decided upon as adverse events that would lead
to study drug discontinuation. However, patient would still be followed to continue safety
monitoring and resolution of adverse events. Any and all adverse events and adverse drug
reactions were evaluated by the principal investigator, who regularly monitored participant
safety to determine which adverse events warranted study discontinuation.
Readmission for reoperation constituted a study endpoint, and data collected at that time-
point will be analyzed as first follow-up data. Hematoma resolution as seen at first follow-up
and discharge from neurosurgical follow-up also constituted a study endpoint.
62
3.5 DATA ANALYSIS
3.5.1 STATISTICAL TEST
For continuous demographic variables, the standard mean difference and confidence
intervals are reported. For normally distributed variables, the Student’s t-test was used to
compare means between the treatment and control groups for continuous variables. Where
data was not normally distributed, the Mann-Whitney U test was used for continuous
variables.
For dichotomous and discrete variables, the Chi-square test was used to compare treatment to
control groups. For dichotomous variables for which the expected cell count was less than 5,
the Chi-square test was invalid, and the Fisher’s exact test was used. For ordinal variables for
which the expected cell count was less than 5, the Chi-square test was invalid, and the Mann-
Whitney U test was used. A p-value <0.05 was considered statistically significant. All
statistical analyses were performed with IBM® SPSS® Statistics Software Version 24 or
with R 3.5.0.
3.5.2 SAMPLE SIZE CALCULATION
Using the data presented by Kageyama et al. (Kageyama et al., 2013), in 18 patients who did
not undergo surgery the median hematoma volume was 55.6 mL (7.5 – 140.5 ml) before
TXA administration and 3.6 mL (22.1 – 0 ml) at the end of follow-up. The mean decrease in
hematoma volume would therefore amount to 53.9 mL. To calculate our sample size, we
used a more conservative estimate of the volume change in each study group: 1=20 mL
(change in hematoma volume in the TXA group) and 2=10 mL (change in hematoma
volume in the control group). Assuming a standard deviation of = 10mL and a power value
of 0.9, we determined that 23 patients would be required per study arm to power the trial
(G*Power 3.1 Software; http://www.gpower.hhu.de/) (Buchner, Erdfelder, Faul, & Lang,
2010). We planned to recruit a sample size of at least 60 patients, 30 in each arm, to account
for attrition.
63
4. RESULTS
4.1 CONSORT FLOW DIAGRAM
Assessed for eligibility (n=183)
Excluded (n=158) Not meeting inclusion criteria (n=106) Declined to participate (n=52) Other reasons (n=0)
Analysed (n=11) Excluded from analysis (n=0)
*Patients with missing data were excluded from some analyses, but included in others
Lost to follow-up (n=1) Discontinued intervention (n=1: patient withdrew consent)
Allocated to TXA (n=12) Received allocated intervention (n=12) Did not receive allocated intervention (n=0)
Lost to follow-up (n=0) Discontinued intervention (n=0)
Allocated to control (n=13) Received allocated intervention (n=13) Did not receive allocated intervention (n=0)
Analysed (n=13) Excluded from analysis (n=0)
Allocation
Analysis
Follow-Up
Randomized (n=25)
Enrollment
64
Figure 8. CONSORT flow diagram. The CONSORT flowchart outlines number of patients screened, number of eligible patients, number of patients recruited, and number of patients included in analysis (Moher, Schulz, Altman, & CONSORT GROUP (Consolidated Standards of Reporting Trials), 2001).
4.2 PARTICIPANT RECRUITMENT AND STUDY FEASIBILITY
We screened all subdural hematoma patients admitted to the neurosurgery department at St.
Michael’s Hospital between February 27, 2017 and January 29, 2018 for patients who met
the study criteria. During this time period, 183 SDH patients were admitted. Of these
patients, 77 were eligible for study enrollment. The most common reasons for study
ineligibility are presented in Figure 9.
*Atrial fibrillation removed as exclusion criterion in July, 2017
Figure 9. Most common reasons for patient ineligibility. The primary reason for patient ineligibility was that they did not undergo operative management of their subdural hematoma. ICH: intracranial hemorrhage; SAH: subarachnoid hemorrhage; CAD: coronary artery disease.
0
5
10
15
20
25
30
Nooperative
management
Atrialfibrillation*
Increasedthrombotic
risk
History ofICH, SAH,
stroke
Alcoholabuse/elicit
drug use
CAD Seizures Mechanicalvalve
Num
ber
of p
atie
nts
Exclusion criteria
65
Over the 11-month study period 25 patients were recruited (Figure 10). One patient
subsequently withdrew consent two days after starting the study drug, leaving a sample size
of 24 patients.
Figure 10. Cumulative participant recruitment. Number of patients recruited (orange) and cumulative enrolment (orange + blue) each month of study period. The overall study recruitment during this period was 32.5%. A decreasing trend occurred
over the study duration, as well as significant fluctuations in month-to-month recruitment
rate (Figure 11). This decreasing trend is contrary to the increasing trend in number of
eligible participants over the study course (Figure 12).
66
*Atrial fibrillation removed as exclusion criterion in July, 2017
Figure 11. Recruitment per month. Overall recruitment for the 11-month study period was 32.5%. Since recruitment of the first patient in March 2017, an overall decreasing trend in recruitment per month was observed, with significant month-to-month variability.
Figure 12. Proportion of eligible patients per month. Overall, there was a general trend towards an increasing number of eligible patients over the study period.
The most common reason for eligible patients to refuse enrollment was disinterest in trial
participation. Other common reasons included concerns regarding risk of side effects; not
wanting to make a decision without consulting their family physician; not wanting to take
0%10%20%30%40%50%60%70%80%90%
Rec
ruitm
ent r
ate
Month
0%
10%
20%
30%
40%
50%
60%
70%
Prop
ortio
n of
pat
ient
s
Month
67
additional medications; feeling they had insufficient time to make a decision regarding
participation; worrying about participation safety for ‘older people’; and not wanting to be
treated as a ‘guinea pig’.
4.3 BASELINE DEMOGRAPHICS AND CLINICAL CHARACTERISTICS
Of the 25 recruited participants, 12 were randomized to the TXA treatment arm, and 13 were
randomized to the control arm. One patient in the TXA arm withdrew consent, leaving 11
patients in the TXA arm and 13 in the control arm. The baseline demographic and clinical
features of the study participants are presented in Table 4.
Table 4. Baseline demographic and clinical characteristics, n (%) or mean (STD) Tranexamic acid
(n=11) Control (n=13)
SMD
Mean age, years 70.18 (12.03) 70.85 (9.31) 0.062 Male 10 (91) 6 (46) 1.055 Weight, kg 81.64 (24.90) 69.42 (18.81) 0.685 Admit GCS 0.395 15 6 (55) 9 (69) 14 3 (27) 3 (23) 13 2 (18) 0 (0) 7 0 (0) 1 (8) Comorbidities Hypertension 6 (55) 10 (77) 0.464 Hypercholesterolemia 4 (36) 4 (31) 0.114 Diabetes mellitus 4 (36) 3 (23) 0.114 Benign prostatic hyperplasia 2 (18) 2 (15) 0.302 Dementia 3 (27) 0 (0) 0.826 Hypothyroidism 0 (0) 2 (15) 0.579 Depression 2 (18) 0 (0) 0.636 Bipolar disorder 0 (0) 1 (8) 0.392 Rheumatic heart disease 2 (18) 0 (0) 0.636 Gout 0 (0) 1 (8) 0.392 Sleep apnea 0 (0) 1 (8) 0.392 GERD 1 (9) 0 (0) 0.426 Stomach ulcers 0 (0) 1 (8) 0.579 Meniere’s disease 0 (0) 1 (8) <0.001 Osteoporosis 0 (0) 1 (8) 0.392 Cancer 0 (0) 1 (8) 0.392 Medications upon admission Anticoagulants 0 (0) 0 (0) <0.001 Antiplatelets 1 (9) 0 (0) 0.426
68
Statins 4 (36) 4 (31) 0.114 Levothyroxine 0 (0) 2 (15) 0.579 Hypotensives 3 (27) 9 (69) 0.886 Hypoglycemics 2 (18) 1 (8) 0.302 Osteoporosis medications 0 (0) 1 (8) 0.422 Proton pump inhibitors 2 (18) 1 (8) 0.302 Uricosurics 1 (9) 1 (8) 0.048 Cholinesterase inhibitors 1 (9) 0 (0) 0.636 Diuretics 0 (0) 1 (8) 0.392 Glucocorticoids 0 (0) 1 (8) 0.392 NSAIDs 0 (0) 2 (15) 0.579 Antidepressants or mood
stabilizers 2 (18) 2 (15) 0.072
Atypical antipsychotic 0 (0) 1 (8) 0.392 Antihistamines 0 (0) 1 (8) 0.392 Dietary supplements 1 (9) 2 (15) 0.185 Melatonin 0 (0) 1 (8) 0.392 Presenting symptoms Headache 4 (36) 7 (54) 0.191 Confusion 3 (27) 3 (23) 0.093 Memory impairment 0 (0) 1 (8) 0.392 Dysarthria 1 (9) 2 (15) 0.185 Gait impairment 7 (64) 1 (8) 1.374 Incoordination 0 (0) 1 (8) 0.392 Weakness 2 (18) 4 (31) 0.443 Hemiparesis 2 (18) 3 (23) 0.072 Facial droop 1 (9) 1 (8) 0.048 Numbness 0 (0) 2 (15) 0.579 Lightheadedness 1 (9) 0 (0) 0.048 Dizziness 2 (18) 3 (23) 0.116 Increased fatigue 3 (27) 1 (8) 0.826 Nausea 0 (0) 2 (15) 0.579 Difficulty sleeping 0 (0) 1 (8) 0.392 Decreased appetite 0 (0) 1 (8) 0.392 Decreased attentiveness 0 (0) 1 (8) 0.392 Disorientation 0 (0) 1 (8) 0.579 History of head trauma 9 (82) 11 (85) 0.072 History of fall 8 (73) 10 (77) 0.074 GCS: Glasgow Coma Scale; GERD: gastroesophageal reflex disease; NSAIDs: non-steroidal anti-inflammatory drugs.
The study groups were comparable in baseline medical comorbidities (Table 4). The most
commonly presenting comorbidities were hypertension (n=16, 67%), hypercholesterolemia
(n=8, 33%), and diabetes mellitus (n=7, 29%).
69
The study groups were comparable in medications being taken upon admission (Table 4).
All medications taken upon admission by study participants were classified according to
medication class or mechanism of action.
With regards to symptoms upon admission, the most frequent presenting symptom was
headache (n=11, 46%). Six patients (24%) presented with some degree of confusion. Eight
patients overall (33%) presented with gait impairment, seven of which were randomized to
the TXA treatment arm (Table 4).
Finally, 20 (83%) patients reported having experienced a minor head trauma ranging from
days, weeks, or months prior to hospital presentation, and 18 of these patients (75%) reported
having had a fall. Head traumas that were not falls included motor vehicle collisions,
collisions during sports, or hitting one’s head on a cabinet or door.
4.4 RADIOLOGIC SUBDURAL HEMATOMA FEATURES
4.4.1 BASELINE RADIOLOGIC CHARACTERISTICS
Radiologic data for the subdural hematomas are presented in Table 5. One patient in the
TXA arm was lost to follow-up, and therefore no follow-up CT scan was available. Further,
the baseline CT scans of two patients in the TXA arm were unavailable at the time of
analysis because their baseline images were taken at outside institutions.
All hematomas at baseline were crescent-shaped. There were no differences in hematoma
laterality between the two study arms. There were more bilateral than unilateral hematomas
in the control arm (n=6, 46%) compared to the treatment arm (n=2, 22%).
The study groups overall were balanced with regards to hematoma location, though just over
half of the hematomas among the control group were located in the fronto-parietal region
70
(n=7, 54%) compared to only 1 (11%) in the TXA group. Altogether, more than half of the
hematomas (n=12, 55%) had frontal, parietal, and temporal involvement.
Table 5. Radiologic hematoma characteristics at baseline, n (%) or mean (STD)
Tranexamic acid (n=9)
Control (n=13) SMD
Laterality 0.315 Left 3 (33) 4 (31) Right 4 (44) 3 (23) Bilateral 2 (22) 6 (46) Hematoma location 0.456 Frontal 1 (11) 0 (0) Fronto-parietal 1 (11) 7 (54) Fronto-parieto-temporal 6 (67) 6 (46) Fronto-parieto-temporo-occipital 1 (11) 0 (0) Hematoma density Heterogeneous 5 (56) 10 (77) 0.441 Hyperdense components 4 (44) 10 (77) 0.670 Isodense components 7 (78) 11 (85) 0.167 Hypodense components 6 (67) 11 (85) 0.228 Septated/loculated 4 (44) 7 (54) 0.180 Fluid-fluid levels 3 (33) 3 (23) 0.218 Appreciable membrane 1 (11) 7 (54) 0.980 Maximum thickness, mm 23.97 (9.27)
26.16 (8.92) 0.241
Maximum anterior-posterior dimension, mm
138.21 (12.91) 136.28 r 13.79 0.144
Midline shift 9 (100) 12 (92) 0.392 Direction of midline shift (left to right)
4 (44) 7 (54) 0.267
Size of midline shift, mm 10.64 7.51 0.641 Sulcal effacement 9 (100) 13 (100) <0.001 Subfalcine herniation 5 (56) 8 (62) 0.116 Brainstem compression 1 (11) 0 (0) 0.471 Cisternal compression 1 (11) 1 (8) 0.111 Ventricular compression 9 (100) 13 (100) <0.001 Hydrocephalus 2 (22) 2 (15) 0.167 Hematoma subtype classification 0.426 I 0 (0) 0 (0) II 3 (33) 4 (31) III 3 (33) 1 (8) IV 1 (11) 2 (15) V 2 (22) 6 (46)
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In both study groups, the majority of hematomas were heterogenous, having hyperdense
components as well as isodensities and hypodensities. Eleven (50%) hematomas had
loculations and septations and six (27%) had fluid-fluid levels. For eight (36%) of the
hematomas overall, a membrane was appreciable on imaging: seven (54%) hematomas in the
control group compared to only one (11%) in the TXA treatment group.
Sulcal effacement and ventricular compression were present on all CT scans, and 4 (18%)
CT scans overall showed some degree of hydrocephalus. Nearly all scans (n = 21, 95%)
showed some degree of midline shift and 11 (46%) produced a shift from left to right. Only
one CT scan (5%) showed brainstem compression and two (9%) showed cisternal
compression.
The hematoma subtype classifications were balanced among the two groups. As expected, no
hematomas in either group were Type I (predominantly hyperdense and acute). Seven (32%)
hematomas were Type II (subacute). Eight hematomas (36%) were classified as Type IV
(heterogenous with septations and loculations). No hematomas were classified as Type VI
(calcifed and hyperdense).
4.4.2 HEMATOMA VOLUME CHANGE OVER STUDY COURSE
Mean hematoma volumes for each study group measured at baseline, immediate
postoperative 4-8 week follow-up, and 8-12 week follow-up are presented in Figure 13.
The volumes on baseline pre-operative and post-operative scans were comparable between
the two study groups (Figure 13, Table 5). Only 5 patients returned for the 8-12 week
follow-up. For all patients who did not return for the second follow-up, their primary treating
neurosurgeon discharged them from neurosurgical care after determining that they were
clinically and radiologically stable.
A.
72
Figure 13. Mean hematoma volume over time. A. For each treatment group, there was an overall trend toward decreasing hematoma volumes over time.
B.
PREOP VOLUME
IMMEDIA
TE POSTOP VOLUME
4-8 W
EEK FU VOLUM
E
8-12 W
EEK FU VOLUM
E-50
0
50
100
150
200
250
Timepoint
Vol
ume (
mL)
Hematoma Volume over Study Duration
Control ArmTXA Arm
73
B. Hematoma volume per participant over the study course shows a trend towards decreasing volume over time, with three participants having larger hematoma volumes at the first follow-up than at baseline. These were three of the four patients in our cohort who required reoperation for hematoma reaccumulation.
Hematoma volume change, calculated as percent hematoma resolution from preoperative to
4-8 week follow-up scan, was slightly higher in the TXA treatment arm (mean = 82.36, STD
= 30.85) compared to the control arm (mean = 75.74, STD = 27.83), however this difference
did not reach statistical significance (Table 6).
Table 6. Procedure type and hematoma volume change over study course, n (%) or mean (STD)
PREOP VOLUME
IMMEDIA
TE POSTOP VOLUME
4-8 W
EEK FU VOLUM
E
8-12 W
EEK FU VOLUM
E0
100
200
300
400V
olum
e (m
L)
Hematoma Volume over Study Duration
74
Tranexamic acid
(n=11)
Control (n=13)
SMD p-value
Preoperative hematoma volume, mL
158.13 (37.32)
153.37 (62.59)
0.092 -
Immediate post-operative hematoma cavity volume, mL
63.75 (36.35) 95.85 (73.75) - 0.469
Hematoma volume at 4-8 week, mL
41.45 (61.98) 61.39 (93.86) - 0.494
Hematoma volume at 8-12 week follow-up, mL
12.30 (15.14) 23.66 (39.28) - 1.000
Percent hematoma resolution from preoperative to 4-8 week follow-up, %
82.36 (30.85) 75.74 (27.83) - 0.219
Percent hematoma resolution from immediate post-operative to 4-8 week follow-up, %
39.54 (86.14) 56.59 (42.63) - 0.852
Patients who did not undergo burr-hole craniostomy underwent mini-craniotomy.
4.4.3 HEMATOMA RECURRENCE RATE AND NEED FOR REOPERATION
Overall, four patients (17%) – two in the TXA treatment arm and two in the control arm –
returned during the study period with re-accumulation of their subdural hematoma requiring
re-operation. There was therefore an 18% recurrence rate in the TXA group, and 15%
recurrence rate in the control group. Both patients from the TXA arm were compliant with
the study drug. The patients in the TXA-group underwent re-evacuation of their re-
accumulated CSDHs seven and six days after initial surgery, respectively. One patient in the
TXA arm was still an inpatient at the time of reoperation, which was performed six days
after the initial procedure. The two patients in the control group underwent re-operation 16
days and 30 days after initial treatment. Both patients from the control arm returned a third
time with recurrent symptoms, but neither underwent a third evacuation surgery.
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4.5 NEUROLOGICAL STATUS ASSESSMENTS AT BASELINE AND 4-8 WEEK
FOLLOW-UP
On most assessments, control patients did not differ from patients in the TXA arm with
respect to neurological status at baseline (Table 7). The study groups did differ in baseline
GCS score, with all control patients (n=13, 100%) having a GCS score of 15, and seven TXA
patients (64%) having a GCS score of 15. Of the patients with GCS scores of 14, three
patients scored four out of five possible points on the verbal response, consistent with some
confusion or disorientation to time, person, or place. One patient scored three out of four
possible points on the eye opening response, consistent with eyes opening in response to
sound as opposed to spontaneously, as they would at a full state of consciousness.
Table 7. Neurological status at baseline and 4-8 week follow-up, n (%)
Baseline assessment 4-8 week follow-up assessment TXA
(n=11) Control (n=13)
SMD TXA (n=10)
Control (n=13)
p-value
GCS total 1.019 0.435 15 7 (64) 13 (100) 9 (90) 13 (100) 14 4 (36) 0 (0) 1 (10) 0 (0) Eye opening 0.426 - 4 10 (91) 13 (100) 10 (100) 13 (100) 3 1 (9) 0 (0) 0 (0) 0 (0) Verbal 0.826 5 8 (73) 13 (100) 9 (90) 13 (100) 4 3 (27) 0 (0) 1 (10) 0 (0) Motor <0.001 - 6 11 (100) 13 (100) 10 (100) 13 (100) GOSE 0.361 0.541 8 4 (36) 7 (54) 8 (80) 8 (62) 7 6 (55) 5 (38) 0 (0) 4 (31) 6 0 (0) 1 (8) 2 (20) 1 (8) 5 1 (9) 0 (0) 0 (0) 0 (0) mRS 0.689 0.708 0 1 (9) 6 (46) 5 (50) 4 (31) 1 6 (55) 4 (31) 3 (30) 8 (62) 2 2 (18) 2 (15) 1 (10) 1 (8) 3 0 (0) 1 (8) 1 (10) 0 (0) 4 2 (18) 0 (0) 0 (0) 0 (0) MGS 0.641 0.586 0 3 (27) 7 (54) 6 (60) 5 (38) 1 5 (45) 5 (38) 2 (20) 7 (54)
76
2 3 (27) 1 (8) 2 (20) 1 (8) NIHSS 0.011 - 0 7 (70)** 11 (85) 9 (100)*** 13 (100) 1 3 (30)** 1 (8) 0 (0) 0 (0) 3 0 (0)** 1 (8) 0 (0) 0 (0) GCS: Glasgow Coma Scale; GOSE: Glasgow Outcome Score, Extended; mRS: modified Rankin Score; MGS: Markwalder Grading Score; NIHSS: National Institutes of Health Stroke Scale. *denotes a statistically significant result. **n=10: one patient was unable to follow commands to complete the NIHSS at baseline. ***n=9: one patient was unable to follow commands to complete the NIHSS at follow-up, and another was lost to follow-up. There were no baseline imbalances in GOSE score between groups. Six patients (25%)
scored zero out of six possible points on the mRS, consistent with being neurologically
asymptomatic (Table 7). Ten patients (42%) overall scored one out of six, consistent with
reporting no significant disability despite some symptoms, and feeling they were able to
carry out their usual duties and activities. Four patients had an mRS score of two at baseline,
feeling slightly disabled, and feeling unable to carry out all previous activities, but able to
look after their own affairs without assistance. One patient in the control group scored an
mRS of three, presenting with moderate disability and requiring some help with activities
and personal affairs, but largely being able to walk without assistance. Two patients, both in
the TXA group, scored an mRS of four, consistent with being moderately to severely
disabled, and unable to walk or attend to bodily affairs without the assistance of others.
There were no baseline imbalances between groups in Markwalder Grading Scores (MGS)
(Table 7). Ten patients (42%) scored zero out of four possible grades, consistent with being
neurologically normal. A further 10 patients received a grade of one, indicating they were
alert and oriented, and had some mild symptoms such as headache or even some minor
neurologic deficit. Four patients (17%) had an MGS of two, indicating they were drowsy or
disoriented with some neurological deficit.
Seventeen patients (74%) of the 23 patients who were able to complete the NIHSS at
baseline scored zero out of 42, consistent with no impairment across any of the tested
functional domains. Four patients (17%) scored one out of 42, a result of disorientation and
77
confusion at baseline. One patient scored three out of 42, resulting from facial hemiparesis
and dysarthria, which were presenting symptoms that persisted after surgery.
At the first follow-up, only one patient was GCS 14, disoriented to time and place (Table 7).
This patient was one of the four patients in our cohort who returned with hematoma growth
that led to reoperation. The remaining patients (96%) were GCS 15.
Table 8. Neurological status change from baseline to 4-8-week follow-up, n (%) TXA
(n=11) Control (n=13)
Baseline
4-8 week follow-up**
p-value Baseline
4-8 week follow-up
p-value
GCS total 0.221 0.083 15 7 (64) 9 (90) 13 (100) 13 (100) 14 4 (36) 1 (10) 0 (0) 0 (0) Eye opening 0.059 0.083 4 10 (91) 10 (100) 13 (100) 13 (100) 3 1 (9) 0 (0) 0 (0) 0 (0) Verbal 0.066 0.083 5 8 (73) 9 (90) 13 (100) 13 (100) 4 3 (27) 1 (10) 0 (0) 0 (0) Motor 0.083 0.083 6 11 (100) 10 (100) 13 (100) 13 (100) GOSE 0.058 1.000 8 4 (36) 8 (80) 7 (54) 8 (62) 7 6 (55) 0 (0) 5 (38) 4 (31) 6 0 (0) 2 (20) 1 (8) 1 (8) 5 1 (9) 0 (0) 0 (0) 0 (0) mRS 0.863 0.062 0 1 (9) 5 (50) 6 (46) 4 (31) 1 6 (55) 3 (30) 4 (31) 8 (62) 2 2 (18) 1 (10) 2 (15) 1 (8) 3 0 (0) 1 (10) 1 (8) 0 (0) 4 2 (18) 0 (0) 0 (0) 0 (0) MGS 0.495 0.040* 0 3 (27) 6 (60) 7 (54) 5 (38) 1 5 (45) 2 (20) 5 (38) 7 (54) 2 3 (27) 2 (20) 1 (8) 1 (8) NIHSS 0.679 0.106 0 7 (70)** 9 (100)*** 11 (85) 13 (100) 1 3 (30)** 0 (0) 1 (8) 0 (0)
78
3 0 (0)** 0 (0) 1 (8) 0 (0) GCS: Glasgow Coma Scale; GOSE: Glasgow Outcome Score, Extended; mRS: modified Rankin Score; MGS: Markwalder Grading Score; NIHSS: National Institutes of Health Stroke Scale. *denotes a statistically significant result. **n=10: one patient was unable to follow commands to complete the NIHSS at baseline. ***n=9: one patient was unable to follow commands to complete the NIHSS at follow-up, and another was lost to follow-up. Sixteen patients (70%) at the 4-8 week follow-up scored an eight on the GOSE, indicating
upper Good Recovery. This was increased from the 11 patients who scored a GOSE of eight
at baseline. Further, four patients scored a GOSE of seven, indicating lower Good Recovery,
an improvement from the 11 patients who were GOSE seven at baseline. No patients scored
less than a GOSE of six at the first follow-up, consistent with upper Moderate Recovery.
Overall, there was no statistically significant difference in 4-8-week follow-up GOSE score
between treatment groups.
There was also no statistically significant difference in mRS, MGS, or NIHSS scores
between groups at the 4-8 week follow-up. Scores on these scales were lower at 4-8 week
follow-up than at baseline, consistent with clinical improvement in neurological status
(Table 8).
Too few patients (n=5) returned for the 8-12 week follow-up to compare neurological status
between groups.
4.6 QUALITY OF LIFE ASSESSMENT SCORES AT BASELINE AND FOLLOW-UP
One patient in the TXA group was unable to complete the questionnaires at baseline, and
another left too many questions incomplete to be scored. One patient in the control group
refused to fill out the questionnaires at both baseline and follow-up. This left 21
questionnaires complete for baseline assessment.
79
4.6.1 SF-36 QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK FOLLOW-
UP
Baseline SF-36 scores across all eight tested domains did not differ between study groups
(Table 9). The control group scored somewhat worse on the ‘Energy and fatigue’ domain
(mean = 10.42, STD = 29.11) than the TXA group (mean = 30.56, STD = 39.09), indicating
lower energy levels and more fatigue. The control group also scored worse on the role
limitations due to physical health domain (mean = 33.41, STD = 32.31) compared to the
TXA group (mean = 51.94, STD = 26.98), indicating they felt more limited in activities they
were able to perform as a result of decreased overall physical functionality. This difference
did not reach statistical significance (0.136).
Table 9. SF-36 scores at baseline and 4-8 week follow-up, mean (STD) Baseline assessment 4-8 week follow-up assessment
SF-36 TXA (n=9)
Control (n=12)
p-value
TXA (n=8)
Control (n=9)
p-value
Physical functioning 42.78 (33.51) 44.77 (32.57) 0.803 50.42 (33.15) 58.89 (26.78) 0.500 Energy and fatigue 30.56 (39.09) 10.42 (29.11) 0.167 21.88 (36.44) 30.56 (32.54) 0.383 Emotional well-being 37.04 (48.43) 33.33 (49.24) 0.739 50.00 (53.45) 51.85 (44.44) 1.000 Social functioning 38.89 (30.19) 37.73 (21.61) 0.970 54.79 (21.05) 58.52 (14.68) 0.662 Pain 54.22 (31.63) 61.09 (19.44) 0.541 74.38 (20.80) 79.33 (15.68) 0.662 General health 47.22 (31.73) 43.75 (30.39) 0.746 57.81 (33.37) 61.11 (27.56) 0.921 Role limitations due to physical health
51.94 (26.98) 33.41 (32.31) 0.136 59.06 (25.74) 74.72 (13.08) 0.143
Role limitations due to emotional health
53.33 (23.85) 68.75 (20.90) 0.108 67.08 (15.09) 64.44 (15.50) 0.743
SF-36: Short-form 36-item health survey. Higher scores indicate a better quality of life for each given category. At the 4-8 week follow-up, the control group had a trend towards better scores than the TXA
group on nearly all tested domains, with ‘Role limitations due to emotional health’ as the
only exception (Table 9). These differences in scores between groups were not statistically
significant.
Table 10. Change in SF-36 scores from baseline to 4-8-week follow-up, mean (STD) TXA
(n=8) Control (n=9)
SF-36 Baseline
4-8 week follow-up
p-value
Baseline
4-8 week follow-up
p-value
Physical functioning 42.78 (33.51) 50.42 (33.15) 0.499 44.77 (32.57) 58.89 (26.78) 0.214 Energy and fatigue 30.56 (39.09) 21.88 (36.44) 0.102 10.42 (29.11) 30.56 (32.54) 0.306
80
Emotional well-being 37.04 (48.43) 50.00 (53.45) 0.655 33.33 (49.24) 51.85 (44.44) 0.748 Social functioning 38.89 (30.19) 54.79 (21.05) 0.173 37.73 (21.61) 58.52 (14.68) 0.078 Pain 54.22 (31.63) 74.38 (20.80) 0.206 61.09 (19.44) 79.33 (15.68) 0.051 General health 47.22 (31.73) 57.81 (33.37) 0.553 43.75 (30.39) 61.11 (27.56) 0.324 Role limitations due to physical health
51.94 (26.98) 59.06 (25.74) 0.207 33.41 (32.31) 74.72 (13.08) 0.035*
Role limitations due to emotional health
53.33 (23.85) 67.08 (15.09) 0.128 68.75 (20.90) 64.44 (15.50) 0.752
SF-36: Short-form 36-item health survey. Higher scores indicate a better quality of life for each given category. *denotes a statistically significant result. 4.6.2 HUI QUESTIONNAIRE SCORES AT BASELINE AND 4-8 WEEK FOLLOW-UP
4.6.2.1 HUI Mark 3
Health utility levels across the eight HUI3 domains – vision, hearing, speech, ambulation,
dexterity, emotion, cognition, and pain – were similar between the control and TXA groups
at baseline (Table 11). Table 11. Frequency distribution of HUI3 single-attribute levels among study participants at baseline and 4-8 week follow-up, n (%) Attribute level
Baseline assessment 4-8 week follow-up assessment TXA (n=9)
Control (n=12)
p-value TXA (n=8)
Control (n=9)
p-value
Vision 0.964 0.665 1 1 (11) 3 (25) 2 (25) 2 (22) 2 8 (89) 7 (58) 6 (75) 7 (78) 3 0 (0) 1 (8) 0 (0) 0 (0) 4 0 (0) 1 (8) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Hearing 0.815 0.735 1 8 (89) 10 (83) 7 (87.5) 8 (89) 2 0 (0) 0 (0) 0 (0) 0 (0) 3 0 (0) 1 (8) 1 (12.5) 1 (11) 4 0 (0) 0 (0) 0 (0) 0 (0) 5 0 (0) 1 (8) 0 (0) 0 (0) 6 1 (11) 0 (0) 0 (0) 0 (0) Speech 0.687 0.122 1 7 (78) 8 (67) 6 (75) 9 (100) 2 0 (0) 0 (0) 1 (12.5) 0 (0) 3 1 (11) 3 (25) 1 (12.5) 0 (0) 4 0 (0) 1 (8) 0 (0) 0 (0) 5 1 (11) 0 (0) 0 (0) 0 (0) 6 N/A N/A N/A N/A Ambulation 0.971 0.369
81
1 4 (44) 4 (33) 5 (62.5) 7 (78) 2 1 (11) 3 (25) 0 (0) 1 (11) 3 0 (0) 2 (17) 2 (25) 1 (11) 4 2 (22) 1 (8) 0 (0) 0 (0) 5 2 (22) 2 (17) 1 (12.5) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Dexterity 0.152 0.080 1 4 (44) 9 (75) 4 (50) 8 (89) 2 2 (22) 1 (8) 3 (37.5) 1 (11) 3 0 (0) 1 (8) 1 (12.5) 0 (0) 4 3 (33) 1 (8) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Emotion 0.739 0.324 1 2 (22) 1 (8) 4 (50) 6 (67) 2 1 (11) 5 (42) 2 (25) 3 (33) 3 4 (44) 4 (33) 2 (25) 0 (0) 4 1 (11) 1 (8) 0 (0) 0 (0) 5 1 (11) 1 (8) 0 (0) 0 (0) 6 N/A N/A N/A N/A Cognition 0.578 0.758 1 0 (0) 1 (8) 4 (50) 4 (44) 2 2 (22) 0 (0) 0 (0) 1 (11) 3 3 (33) 3 (25) 1 (12.5) 2 (22) 4 2 (22) 6 (50) 2 (25) 2 (22) 5 1 (11) 2 (17) 1 (12.5) 0 (0) 6 1 (11) 0 (0) 0 (0) 0 (0) Pain 1.000 0.168 1 0 (0) 0 (0) 5 (62.5) 0 (0) 2 1 (11) 3 (25) 0 (0) 6 (67) 3 4 (44) 2 (17) 3 (37.5) 3 (33) 4 1 (11) 3 (25) 0 (0) 0 (0) 5 3 (33) 4 (33) 0 (0) 0 (0) 6 N/A N/A N/A N/A N/A: not applicable. Scores range from 1 to 6, lower scores indicating perfect health and higher scores indicating worse health.
Based on the baseline attribute levels, one of the most severely affected health attributes in
the week prior to questionnaire completion was pain, with all patients in both study groups
reporting some degree of pain, and no patients scoring perfect health (a score of one).
Likewise, all but one study patient had some degree of cognitive impairment. Eighteen
patients (86%) had impaired emotional faculties, and 13 (62%) had impaired ambulation. Six
patients (29%) had some degree of speech impairment, and eight (38%) had impaired
dexterity. Three patients had impaired hearing at baseline, all of which were consistent with
age-related hearing loss.
82
At the 4-8 week study follow-up, there was again no difference in HUI3 utility level scores
between control and TXA patients (Table 11). Compared to baseline assessments, patients in
both study groups had lower scores on pain, cognition, speech, and ambulation, indicating
improved health across those domains.
There were no baseline imbalances between study groups in the overall HUI3 multi-attribute
health related quality of life (HRQL) utility scores, which were derived from the single-
attribute scores (Table 12, Figure 14A and B). No patients in either group reported perfect
health (an HRQL score of 1). Three patients in the control group and three patients in the
TXA group had multi-attribute HRQL scores below zero, indicating a quality of life self-
rated worse than death. Table 12. Mean overall HUI3 multi-attribute HRQL utility scores at baseline and 4-8 week follow-up, mean (STD) Baseline assessment 4-8 week follow-up assessment TXA
(n=9) Control (n=12)
p-value TXA (n=8)
Control (n=9)
p-value
HUI3 HRQL 0.23 (0.38) 0.27 (0.33) 0.831 0.61 (0.39) 0.76 (0.12) 0.791
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Figure 14. Frequency distribution of overall HUI3 Multi-attribute (HRQL) Utility Scores. Scores are presented at baseline for (A) TXA-treated participants, and (B) control participants, and at follow-up for (C) TXA-treated participants, and (D) control participants. An optimal HRQL score is closer to 1, with 1 indicating perfect health.
The mean overall HUI3 multi-attribute HRQL utility scores at 4-8 week follow-up did not
differ significantly between the two groups (Table 12, Figure 14B and C). No patients had
HRQL scores below zero, compared to six patients at baseline.
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Compared to baseline, the mean overall HUI3 HRQL scores at 4-8 week follow-up were
higher, though this improvement only reached statistical significance in the control group
(Table 13, Figure 14B and C). At 4-8 week follow-up, no patients had HRQL scores below
zero, compared to six patients at baseline.
Table 13. Change in overall HUI3 multi-attribute HRQL utility scores from baseline to 4-8 week follow-up, mean (STD) TXA
(n=9) Control (n=12)
Baseline 4-8 week follow-up**
p-value Baseline 4-8 week follow-up***
p-value
HUI3 HRQL 0.23 (0.38) 0.61 (0.39) 0.128 0.27 (0.33) 0.76 (0.12) 0.008 **n=8. ***n=9. Conversion of these HRQL scores to disability categories showed that most patients were
severely impaired across the HUI3 health attributes at baseline (Table 14). No patients had
perfect overall health or even mild impairment.
Table 14. Frequency distribution of disability category based on overall HUI3 Multi-attribute (HRQL) Utility Score at baseline and 4-8 week follow-up, n (%) Baseline assessment 4-8 week follow-up assessment Disability Category TXA
(n=9) Control (n=12)
p-value TXA (n=8)
Control (n=9)
p-value
Mild 0 (0) 0 (0) 0.686 3 (37.5) 1 (11) 0.815 Moderate 1 (11) 1 (8) 2 (25) 6 (67) Severe 8 (89) 11 (92) 3 (37.5) 2 (22) At the 4-8 week follow-up, the study groups did not differ significantly in HUI3 disability
category (Table 14). While five patients (31%) were still categorized as having severe
disability at 4-8 week follow-up, four patients (25%) were categorized as having mildly-
impaired overall function across the eight HUI3 health attributes compared to zero patients at
baseline.
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4.6.2.2 HUI Mark 2
Single-attribute healthy utility levels across the seven HUI2 domains – sensation, mobility,
cognition, self-care, emotion, pain, and fertility – were similar between the control and TXA
groups at baseline (Table 15). Similar to HUI3 level scores, 23 patients had some level of
impairment in cognition and pain. Further, sensation was also impaired in all but one study
patient. Thirteen patients (62%) were impaired to some degree in their ability to maintain
self-care.
Table 15. Frequency distribution of HUI2 single-attribute levels among study participants at baseline and 4-8 week follow-up, n (%) Attribute level
Baseline assessment 4-8 week follow-up assessment TXA (n=9)
Control (n=12)
p-value TXA (n=8)
Control (n=9)
p-value
Sensation 0.493 0.495 1 0 (0) 1 (8) 2 (25) 2 (22) 2 7 (78) 5 (42) 4 (50) 7 (78) 3 1 (11) 6 (50) 2 (25) 0 (0) 4 1 (11) 0 (0) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Mobility 0.911 0.369 1 4 (44) 4 (33) 5 (62.5) 7 (78) 2 1 (11) 3 (25) 0 (0) 1 (11) 3 2 (22) 3 (25) 2 (25) 1 (11) 4 2 (22) 2 17) 1 (12.5) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Cognition 0.475 0.957 1 0 (0) 1 (8) 4 (50) 4 (44) 2 7 (78) 9 (75) 3 (37.5) 5 (56) 3 1 (11) 2 (17) 1 (12.5) 0 (0) 4 1 (11) 0 (0) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Self-care 0.702 0.426 1 4 (44) 5 (42) 6 (75) 8 (89) 2 4 (44) 4 (33) 1 (12.5) 1 (11) 3 0 (0) 1 (8) 1 (12.5) 0 (0) 4 1 (11) 1 (8) 0 (0) 0 (0) 5 0 (0) 2 (17) 0 (0) 0 (0) 6 N/A N/A N/A N/A Emotion 0.236 0.173 1 1 4 (33) 4 (50) 7 (78) 2 3 5 (42) 2 (25) 2 (22) 3 4 1 (8) 2 (25) 0 (0) 4 1 1 (8) 0 (0) 0 (0)
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5 0 (0) 1 (8) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Pain 0.331 0.261 1 0 (0) 1 (8) 5 (62.5) 1 (11) 2 5 (56) 4 33) 1 (12.5) 8 (89) 3 3 (33) 2 (17) 2 (25) 0 (0) 4 1 (11) 2 (17) 0 (0) 0 (0) 5 0 (0) 3 (25) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) Fertility 1.000 1.000 1 9 (100) 12 (100) 8 (100) 9 (100) 2 0 (0) 0 (0) 0 (0) 0 (0) 3 0 (0) 0 (0) 0 (0) 0 (0) 4 0 (0) 0 (0) 0 (0) 0 (0) 5 0 (0) 0 (0) 0 (0) 0 (0) 6 0 (0) 0 (0) 0 (0) 0 (0) N/A: not applicable. Scores range from 1 to 6, lower scores indicating perfect health and higher scores indicating worse health. At the 4-8 week follow-up, more patients had lower levels of pain than at baseline, with six
patients (35%) reporting no pain at all (Table 15). There were also nearly twice as many
patients (n=14, 82%) with no self-care limitations at the 4-8 week follow-up compared to at
baseline (n=9, 43%). Overall, patients between treatment groups did not differ significantly
across the HUI2 attribute levels at the 4-8 week follow-up.
There was no difference in overall HUI2 multi-attribute HRQL utility scores between study
groups at baseline or at 4-8 week follow-up (Table 16, Figure 15).
Table 16. Mean overall HUI2 multi-attribute HRQL utility scores at baseline and 4-8 week follow-up, mean (STD) Baseline assessment 4-8 week follow-up assessment TXA
(n=9) Control (n=12)
p-value TXA (n=8)
Control (n=9)
p-value
HUI2 HRQL 0.55 (0.24) 0.50 (0.27) 0.570 0.72 (0.27) 0.87 (0.07) 0.632
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Figure 15. Frequency distribution of overall HUI2 Multi-attribute (HRQL) Utility Scores. Scores are presented at baseline for (A) TXA-treated participants, and (B) control participants, and at follow-up for (C) TXA-treated participants, and (D) control participants. An optimal HRQL score is closer to 1, with 1 indicating perfect health.
Similar to the HUI3 HRQL utility scores, the HUI2 HRQL scores were higher at the 4-8
week follow-up than at baseline (Table 17). This change reached statistical significance in
the control group but not the TXA group. However, this change may still suggest a clinically
relevant improvement in functionality across the HUI2 levels.
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Table 17. Change in overall HUI2 multi-attribute HRQL utility scores from baseline to 4-8 week follow-up, mean (STD) TXA
(n=9) Control (n=12)
Baseline 4-8 week follow-up**
p-value Baseline 4-8 week follow-up***
p-value
HUI2 HRQL 0.55 (0.24) 0.72 (0.27) 0.176 0.50 (0.27) 0.87 (0.07) 0.008* *denotes a statistically significant result. **n=8. ***n=9.
Finally, the distribution of disability categories based on HUI2 attributes showed that most
patients (n=19, 90%) were severely impaired across these health domains, 2 (10%) were
moderately impaired, and no patients were at full or at least mild health utility (Table 18).
Table 18. Frequency distribution of disability category based on overall HUI2 Multi-attribute (HRQL) Utility Score at baseline, n (%) Baseline assessment 4-8 week follow-up assessment Disability Category TXA
(n=9) Control (n=12)
p-value TXA (n=8)
Control (n=9)
p-value
Mild 0 (0) 0 (0) 0.686 2 (25) 3 (33) 0.539 Moderate 1 (11) 1 (8) 3 (37.5) 4 (44) Severe 8 (89) 11 (92) 3 (37.5) 2 (22) At the 4-8 weeks follow-up, five patients (31%) were classified as having severely impaired
functionality across HUI2 health attributes compared to 19 patients (90%) at baseline (Table
18). While no patients at baseline had better than moderate functionality, at follow-up, four
patients (67%) were categorized as having only mild impairment. There was no significant
difference between treatment groups in frequency distribution of disability categories at 4-8
weeks.
4.7 ADVERSE EVENTS AND TXA SAFETY
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The number of expected and unexpected adverse events experienced by patients in the
control group did not differ significantly from the number experienced by patients in the
TXA treatment arm (Table 19). There were no serious unexpected adverse events.
Headache was the most frequently reported adverse event (n = 6, 25%), and was most
commonly reported in the acute period after surgery, often resolved or highly infrequent by
the time of the 4-8 week clinical follow-up.
Table 19. Frequency of adverse events and serious adverse events during study period, n (%)
AE or SAE TXA (n=11) Control (n=13) p-value Weakness 0 (0) 1 (8) 1.000 Headache 2 (18) 4 (31) 0.649 Sinus pain 1 (9) 0 (0) 0.458 Jaw pain 1 (9) 0 (0) 0.458 Dysphagia 1 (9) 0 (0) 0.458 Acute swelling 2 (18) 0 (0) 0.199 Dry skin on scalp 1 (9) 0 (0) 0.458 Intermittent dizziness 1 (9) 2 (15) 1.000 Shortness of breath 0 1 (8) 1.000 Chest pain 0 1 (8) 1.000 Nausea or stomach upset 1 (9) 1 (8) 1.000 Stomach pain 0 2 (15) 0.482 Bladder infection 1 (9) 0 (0) 0.458 Muscle pain 1 (9) 0 (0) 0.458 Back pain 0 0 (0) 1.000 Seizure 1 (9) 0 (0) 0.458 Fatigue 1 (9) 2 (15) 1.000 Attention and memory impairment
1 (9) 0 (0) 0.458
Hematoma recurrence requiring revision surgery
2 (18) 2 (15) 1.000
AE: adverse event; SAE: serious adverse event.
While not significantly different between groups, some adverse events, such as shortness of
breath, chest pain, and generalized weakness were experienced only by control patients,
while others, including dysphagia, jaw pain, sinus pain, dry skin, muscle pain, bladder
infection, and attention and memory impairment were only experienced by patients in the
TXA group. Acute swelling was also experienced by two patients in the TXA group: in the
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jaw of one patient, and in the left ankle of the other. Two patients (8%) experienced nausea
or stomach upset.
No patients reported experiencing an allergic reaction to TXA. No patients reported sudden
or unexpected visual disturbances, and no retinal changes were detected. While one patient
experienced some intermittent dizziness, no patients experienced persistent dizziness or long-
lasting hypotension.
No patients experienced thrombotic or thromboembolic events, including cerebral infarction
or thrombosis, myocardial infarction, angina, deep vein thrombosis or arterial thrombosis.
No changes in renal function or urination were reported.
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5. DISCUSSION
5.1 BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
The baseline demographic and clinical characteristics were largely balanced between the two
groups. There was, however, an imbalance in sex between the two groups, with more males
in the TXA treatment arm than the control arm. This observed difference was attributed to
the small sample size, and may balance out with increased recruitment. It is also important to
note that many studies have reported a predominance in incidence and prevalence of SDHs in
males compared to females (Baechli, Nordmann, Bucher, & Gratzl, 2004). Likewise at our
institution, 79% of admitted SDH patients were male, and 70% of eligible SDH patients were
male. Demographic differences among patients likely follows from the heterogeneity of the
natural disease course.
Comorbidities at baseline were also balanced between the two groups. The most frequent
comorbidities were hypertension, hypercholesterolemia, and diabetes mellitus, which is
consistent with some of the most common chronic health diseases suffered by senior
populations (Salive, 2013).
No patients in our study were taking anticoagulants upon admission, and only two (8%) were
taking antiplatelets (neither of these patients were restarted on antiplatelets by their treating
physician until after the follow-up and study period, to mitigate the risk of re-bleeding).
Given the senior demographic of our study population, we expected more patients to be
taking these medications for other comorbidities. It is likely that most patients with
comorbidities that would have entailed anticoagulant treatment – including coronary artery
disease (CAD), recent ischemic stroke, or other medical condition causing an increased
thrombotic risk – were excluded upon screening, based on our predefined eligibility criteria.
Expanding the eligibility criteria to include these patients may lead to greater recruitment of
patients taking anticoagulants and antiplatelets. However, these clinical variables would have
to be controlled for as they are potential risk factors for SDH development and recurrence,
and may potentially confound the secondary outcome measure.
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20 patients (83%) reported some history of head trauma in the weeks or months prior to
admission. This is consistent with the fact that more than 60% of CSDH patients report a
history of minor head trauma (Sousa et al., 2013), making head trauma one of the leading
risk factors for CSDH. The incidence of falls and head traumas among seniors is rising as our
population ages (Cigolle et al., 2015; Taylor, Bell, Breiding, & Xu, 2017). This increases not
only the risk of CSDH development, but potentially the risk of postoperative recurrence,
especially if patients experience unstable gait or dizziness after surgery.
5.2 RADIOLOGIC SUBDURAL HEMATOMA CHARACTERISTICS
The radiologic characteristics did not differ significantly between the two study groups at
baseline. Most hematomas (n=15, 60%) were heterogenous, and eleven (50%) were loculated
or septated on the preoperative scan. Hematomas with these separated and heterogenous
features have been associated with a higher tendency to rebleed and possibly increased
potential to recur postoperatively (Nakaguchi, Tanishima, & Yoshimasu, 2001; Stanišić et
al., 2013), though the number of patients in our cohort who experienced a recurrence was too
small to detect an association between these radiologic features and recurrence.
5.3 PRIMARY OUTCOME
5.3.1 STUDY FEASIBILITY AND RECRUITMENT RATE
We believe that we have demonstrated that conducting a clinical trial investigating the
efficacy of TXA therapy in post-operative patients is feasible at our institution. Despite not
reaching our target sample size, study procedures were largely unremarkable, and therefore
with respect to the study procedures and technicalities, we were able to carry out this pilot
trial at our institution. As discussed below, improvements to our recruitment methods to
enhance participant recruitment would be ideal to demonstrate the feasibility of conducting a
larger, multi-center trial.
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Of the 189 patients admitted to St. Michael’s Hospital with SDH over the 11-month time
period during which the patients in our cohort were recruited, 77 (41%) were eligible, and we
were able to recruit 32.5% of these patients, with one patient subsequently withdrawing
consent. With this overall recruitment and given the average number of SDH patients
admitted to St. Michael’s Hospital annually, it is reasonable to expect that we would be able
to reach the 46-person sample size needed to sufficiently power the study within a
conservative estimate of approximately 12 more months of recruitment.
In order to establish the foundations of a feasible trial, we first needed to ensure that all of
the various study procedures could operate smoothly at our site. Therefore, prior to study
initiation, we met with the clinical nurse managers, educators, clinical pharmacists, research
pharmacists, and CT department technicians to discuss details of the study procedures. These
meetings informed the development of our study Standard Operating Procedures (SOPs).
After procedures and SOPs were established, we held training sessions for all pertinent staff
with direct involvement in study procedures, namely the research pharmacists, RNs, and
clinical pharmacists, who would be directly involved in ordering, dispensing, documenting,
and administering the study IP to patients. These training sessions were led by the study PI,
and included a visual presentation with slide decks, as well as opportunities for staff to ask
questions.
The study procedures, mostly pertaining to IP dispensation by the research pharmacists and
IP administration to inpatients by the RNs on the neurosurgery ward, ran largely without
issue over the study course. For instance, during feedback sessions, no RNs reported having
difficulty finding the study IP in the designated temperature-monitored drug box.
We found that all study procedures were facilitated with regular reinforcement and reminders
from the study coordinator. For instance, we regularly needed to remind RNs that participant
weights needed to be documented in the medical chart, not only for accurate IP dosing but
for the purposes of source documentation. There was often a discrepancy as RNs assumed
the weight would be documented in the anaesthesia record or operating room report, but
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rarely was. These discrepancies in clinical and study procedures were resolved with regular
oversight by the study coordinator.
One procedural difficulty we faced was with regards to standardizing the CT scan protocol.
Despite our efforts ensure all patients were scanned with the GE Revolution scanner at
follow-up, including specifying this study protocol directly on the CT order form, this was
not always possible. This was due to the restricted availability of the scanner. At our
institution, this is the scanner used for trauma patients, preoperative imaging following the
BrainLab protocol, or other priority scans, which take precedence. Therefore, if the machine
was not available at the time of the patient’s follow-up scan, the imaging was performed by
the other available CT scanners.
While these efforts yielded an overall recruitment just above 30%, which would in theory be
sufficient to reach our recruitment goal, it would be ideal to improve the recruitment rate as
much as possible. Failing to recruit enough patients to a clinical trial substantially limits the
power of the study to detect a minimal clinically important difference, and therefore the
study’s potential to impact the clinical problem in question. Low recruitment rates and
encouraging trial participation among patients are challenges that have long been faced by
clinical trial sites. In fact, a review of 151 randomized controlled trials found that the median
recruitment rate was less than one patient per site per month (Walters et al., 2017). Further,
attrition and participant drop-out rates are also a significant problem, particularly for longer
trials where study follow-ups extend over the course of months or years.
In an effort to improve recruitment, we first repeated the training sessions with the
neurosurgery RNs, pharmacists, and staff, ensuring that everyone involved in key study
procedures was aware of their roles. Every time there was a change in study protocol,
pertinent staff were informed of the changes to ensure smooth operation of study procedures.
These training sessions, in addition to regular communication with the study coordinator,
seemed to encourage RN involvement in the study. Soon after training sessions, RNs
occasionally told the study coordinator is a CSDH patient was admitted under their care,
which was helpful to ensure all consecutively-admitted patients were screened for eligibility.
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Based on this, we found that regular communication, particularly with the RNs, boosted their
involvement in the study.
We also re-examined our original study exclusion criteria in an attempt to increase the
number of eligible patients at our site. After extensive literature searches and clinical
consultations, we determined our initial criteria to be overly-restrictive, and in July 2017
modified the exclusion criteria to be less restrictive. For instance, we removed atrial
fibrillation as an exclusion criterion, which was one of the most significant contributors to
patient ineligibility. Atrial fibrillation is not listed as a contraindication on the TXA product
monograph. Further, the use of TXA may be useful in mitigating the risk of major bleeding
in patients with atrial fibrillation who are taking novel oral anticoagulants (NOACs), without
increasing the risk of a major thrombotic event (Kowey, Piccini, Naccarelli, & Reiffel,
2017). We found that following this change, the number of eligible SDH patients increased
steadily over time (Figure 11). Despite this however, our recruitment rate still showed a
decreasing trend. This suggested that increasing the proportion of eligible patients alone
would not be sufficient in improving our recruitment rate.
Others have gone to great lengths to identify the best quality improvement strategies for
improving recruitment rates in clinical trials (Sauers-Ford et al., 2017; Sauers, Beck, Kahn,
& Simmons, 2014). The most effective strategies appear to be holding regular (ideally,
weekly) meetings with key trial stake-holders to reflect on recruitment rates and procedures,
as well as barriers to recruitment. These meetings also serve as platforms for
multidisciplinary input, feedback, and discussion, which contribute to well-thought out
recruitment strategies. Engaging key staff and personnel in particular is crucial, as quality
improvement among study staff requires their leadership and oversight. While these
initiatives have been shown to be very effective (Sauers-Ford et al., 2017; Sauers et al.,
2014), they are unfortunately quite time-intensive. Arranging weekly meetings with trial co-
investigators, especially if multiple sites are involved, proves a nearly impossible task in the
wake of busy clinical schedules. Arranging regular meetings with the co-investigators proved
difficult due to conflicting and busy schedules, however, we did see a positive effect when
the study coordinator spoke to the co-investigators about their eligible patients, whether to
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discuss eligibility or simply to update them on trial status. These conversations served as
frequent reminders of the ongoing study, seemingly encouraging the investigators to tell the
study coordinator that a CSDH patient had been admitted under their care. However, this did
not encourage the co-investigators to speak to the patients about the study, even when
reminded by the study coordinator. While we would have hoped these efforts would have
encouraged greater involvement from the study co-investigators, this did again demonstrate
the positive effects of regular oversight of study procedures and communication from the
study coordinator in conducting the clinical trial.
In order to improve recruitment rates, we undertook several other quality improvement
initiatives. Beginning with increasing staff awareness and engagement, we hosted quality
improvement “huddles” with key staff – namely RNs and clerical personnel – on the
neurosurgery ward, providing study updates as well as receiving their feedback and
perspective on the clinical trial feasibility on the ward, including their suggestions for
increasing staff engagement. We presented the trial to neurosurgery residents and staff at
neurosurgery teaching rounds, roughly every 6-months, updating them on trial status to
engage them in participation. This was done at key time-points, such as when new residents
arrived at our institution. We also used more visual reminders, hanging posters on the
neurosurgery ward in areas frequented by staff and nurses, and sending regular updates on
the current trial status and our goals for completion. The most effective of these initiatives
were the staff “huddles” with the RNs, which seemed to boost their enthusiasm for the study
and serve as reminders that the study was ongoing. Despite these efforts to encourage
neurosurgery resident involvement, we found the best strategy was if the study coordinator
asked them to introduce the study to a potentially eligible patient while they were rounding
on patients on the ward. Otherwise, residents rarely introduced the study to patients without a
direct reminder, which we understand given the demands of their primary clinical work.
We also focused on mitigating patient-specific barriers to recruitment, particularly on
eliminating modifiable reasons for non-recruitment. We found that questions asked during
the consent discussion revealed some of the most common concerns patients had about trial
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participation, and reasons they would ultimately refuse consent. Some of the most commonly
asked questions during the consent discussion were:
· What are the side-effects?
· Is it safe to take this medication alongside the ones I am already taking?
· I live far away – if I participate, how many times would I have to come back to
the hospital?
· Is the medication safe for older people?
· Can I make an appointment with my family doctor and discuss this with him/her
before making a decision?
· Can I have more than couple of days to decide?
Based on these insights, we used several communication strategies when engaging in the
consent discussion to mitigate these modifiable reasons for refusing to enroll in the trial.
Safety was evidently one of the biggest concerns among patients. We therefore found that
introducing the study to patients by study co-investigators or physicians within their circle of
care made them less ‘skeptical of the experimental nature’ of the medication. Further,
emphasizing the potential benefits of trial participation, such as closer neurological follow-
up, seemed to counter some of the anxiety patients had about potential risks and side-effects.
Some of the most common reasons for refusal to participate were related to advanced age,
which is our primary target population. We found that despite clarifying the natural history
of subdural hematomas and their higher incidence in senior populations, many eligible
patients still refused participation on the basis of their age. The difficulties of recruiting
elderly patients to clinical trials have been extensively discussed in the literature (Cassidy,
Baird, & Javaid Sheikh, 2001; Macias, Ramsay, & Rowan, 2007; McHenry et al., 2015), and
are of increasing concern now, as our population is rising at an unprecedented rate. There is
therefore a need now more than ever to focus on medical interventions in senior age groups.
Distrust, caregiver burden, medical concerns, and barriers to transportation are all recognized
reasons for refusal to participate among senior patients (Crawford Shearer, Fleury, & Belyea,
2010; Gonzalez, Gardner, & Murasko, 2007; Ory et al., 2002; Saunders, Greaney, Lees, &
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Clark, n.d.). While incentives have been used in some studies to overcome some of these
barriers (Gonzalez et al., 2007), building a trusting relationship between the research team
and the patient seems to be the most substantial, albeit difficult, way to improve recruitment
among the elderly. In fact, on study suggested that a potential method for improving
recruitment rate among seniors is by maintaining a close relationship with general
practitioners, who can refer their senior patients – with whom they have an established
patient-physician relationship – to actively-recruiting clinical trials (Cassidy et al., 2001).
This suggests that support from a senior patient’s family doctor with whom they have a
trusting rapport may encourage study participation.
5.3.2 STUDY DRUG COMPLIANCE AND OUTCOME MEASURE
COMPLETION
We found that the dosing regimen supported drug compliance, and therefore feasibility of
this trial. Based on the drug diaries and remaining tablets returned to us from study patients,
we had no problems with drug compliance. In the event a dose was missed, patients were
able to follow the instructions for handling missed doses without issue. We believe that
having oral tablets that patients did not need to break, and that could be taken with meals,
made the study IP easily introducible into the patients’ existing medication regimens,
contributing to study drug compliance.
The dosing regimen also proved feasible if patients were repatriated or discharged to a
rehabilitation centre before returning home. Nineteen patients were discharged home, five
were discharged to a rehabilitation centre, and one was repatriated to another hospital. In
fact, patients who were repatriated or discharged to a rehabilitation centre were less likely to
miss a dose because TXA was administered by RNs or other staff at these institutions.
We also had few problems with completion of the 4-8 week clinical follow-up. Coordinating
the trial so that it coincided with clinical follow-up helped us ensure that all but one patient
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returned for the follow-up CT scan, yielding an attrition rate of 4%. It also aided the
recruitment process, where most patients stated they would have refused study participation
if extra visits were required. Also, some patients were fearful of the radiation exposure
associated with CT scans; by using the clinical CT scan, the patients did not have to undergo
more scans than clinically necessary.
Moreover, patients did not report having difficulty completing the questionnaires, and if they
were unable to do so, had a family member or proxy complete it with their help. The self-
completion nature of the SF-36 and HUI assessments – as well as the option to have the
HUI3 completed by a proxy – in general aided in the feasibility of this trial. Overall, most
patients reported no trouble completing the questionnaires in a timely way, and did not report
feeling stressed or overwhelmed in doing so. This allowed the patients to complete the
questionnaires at their discretion for as long as they needed, and also allowed for a family
member to help complete it if the patient felt too unwell to do so. However, not all patients
were compliant in completing the QOL assessments. One patient in the control group refused
to fill out the questionnaires altogether. Some patients felt too unwell to try to complete it at
baseline, and asked to fill it out at home when they could have more time to think about their
answers. In these situations, the study coordinator followed up with the patients soon after
discharge to ensure it was completed, then again before the follow-up appointment to remind
them to return the questionnaire – this was often, but not always, sufficient. Some patients
forgot to complete baseline questionnaires while inpatients, however, reminders by the study
coordinator ensured that these patients filled them out before discharge. Altogether, it seems
persistent reminders from the study coordinator were beneficial in ensuring that
questionnaires were completed.
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5.4 SECONDARY OUTCOMES
5.4.1 HEMATOMA VOLUME CHANGE FROM BASELINE TO FOLLOW-
UP
The baseline hematoma volumes and postoperative hematoma cavity volumes are consistent
with values reported in the literature (Stanišić et al., 2013). Though the difference was not
statistically significant, the mean immediate post-operative hematoma volume was higher in
the control group than the TXA group. This could have contributed to the lower degree of
hematoma resolution in the control group compared to the treatment arm.
The ‘gold standard’ hematoma measurement technique has been compared to, and found to
be more accurate than, other mathematical estimates of hematoma volume (Stanišić, Groote,
Hald, & Pripp, 2014). It is important to note however that despite our best efforts, not all CT
scans could be performed on the same machine, and therefore volumes calculated from
thinner slices (for instance, 1.25 mm compared to 5mm) may yield more precise volume
estimates than those calculated from thicker slices. Therefore, given the small sample size,
small differences in volume may affect the volume comparison between groups.
The percent resolution from the preoperative to 4-8 week follow-up scan was slightly greater
in the TXA treatment arm compared to the control arm, however this difference did not reach
statistical significance. It is therefore possible that with a larger sample size with complete
data available, this trend may reach statistical significance. These results also inform the
feasibility of a future, double-blind trial. When calculating the sample size needed to power
this pilot, we estimated a hematoma volume change of 10 mL in the control group and 20 mL
in the TXA-treated group. Our results showed that the mean decrease in hematoma volume
in millilitres from baseline to 4-8 week follow-up was 92.0 mL in the control group, and
143.49 mL in the TXA-treated group. With respect to the TXA-treated group, this volume
decrease is more than twice that reported by Kageyama et al., whose data were used in our
sample size calculation (Kageyama, Toyooka, Tsuzuki, & Oka, 2013). However, it is
important to note that Kageyama et al. investigated the efficacy of TXA treatment in non-
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surgical treatment. Therefore, it is reasonable that our hematoma volume change would be
larger as our patients first underwent surgical evacuation.
The standard post-operative follow-up time period for subdural hematoma is between 4-8
weeks, with the variation a result of the surgeon’s clinical opinion and clinical availability.
Patients are discharged because they are clinically asymptomatic, and no longer require
neurosurgical intervention or follow-up, often regardless of whether or not there is still a
residual hematoma as seen on the CT scan. Therefore most study patients were discharged
from neurosurgical care at the first follow-up. However, most patients still had residual
hematoma at the first follow-up: only four patients – two in the TXA group and two in the
control group – had complete hematoma resolution on the 4-8 weeks follow-up scan. They
were discharged because their treating neurosurgeon felt that given the degree of hematoma
resolution and stable clinical presentation, they no longer required neurosurgical follow-up.
To date, none of these discharged patients have returned to our institution for continued
follow-up of their CSDH. Further, of the five patients who returned for the 8-12 week
follow-up, one had complete resolution at this time point. The subset of patients with
complete resolution was insufficient to produce a Kaplan-Meier curve comparing time to
complete resolution between the two groups. Further, because patients with residual
hematoma were discharged from neurosurgical care, it is unclear if and when their
hematomas completely resolved.
5.4.2 HEMATOMA RECURRENCE AND REOPERATION RATE
Four patients (17%) in the study cohort – two from each treatment group – experienced re-
accumulation of their CSDH requiring repeat surgical evacuation. Three patients returned to
our institution seven days, 16 days, and 30 days after discharge from initial hospital stay.
One patient in the TXA arm was still an inpatient at the time of reoperation, which was
performed six days after the initial procedure. The two patients in the control group each
returned a third time, twenty-two and forty days after discharge from their initial hospital
visit. One of these patients returned with symptoms consistent with CSDH accumulation, but
did not undergo a third evacuation procedure. The other returned with stroke-like symptoms,
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and was briefly admitted to the neurology unit where a workup confirmed he did not have a
stroke.
This small number of outcomes, in addition to the small sample size, was insufficient to
carry out a Kaplan-Meier analysis on time to recurrence. Larger sample sizes sufficient to
power the study would be needed to detect a statistically significant difference in recurrence
rate between the groups, therefore, a conclusion as to whether there is a correlation between
TXA and reduced hematoma recurrence cannot be supported by our findings. Despite this,
the 17% overall recurrence rate in our cohort is consistent with CSDH recurrence rates
reported in other reports (Abouzari et al., 2007; Qian, Yang, Sun, & Sun, 2017; Santarius et
al., 2009).
5.4.3 NEUROLOGICAL STATUS FROM BASELINE TO FOLLOW-UP
There was largely no statistically or clinically significant difference in neurological status
between the two groups at baseline or at 4-8 week follow-up. At baseline however, control
patients did differ from the TXA group in total GCS score: all patients in the control arm
were GCS 15 at baseline, compared to 64% of patients in the TXA arm. The remaining 36%
of patients had a GCS of 14. Despite the statistical significance of this difference, the
difference is not likely to be clinically significant. It is common for the level of
consciousness to fluctuate in neurosurgery patients both before and after surgery, particularly
between GCS 15 and 14. This is often due to some confusion or disorientation to date, time,
or place, leading to a verbal component score of four rather than five and subsequent overall
GCS score of 14 rather than 15. This was in fact the case for three of the four patients in the
TXA arm with a baseline GCS of 14.
Scores on the neurological status assessments improved from baseline to follow-up in both
groups. The only statistically-significant improvement was seen in the control group on the
MGS. This could potentially be due to a small sample size that is insufficient to power the
test. Improvement in neurological status is clinically expected from baseline to follow-up,
and while most improvements were not statistically significant, this does not mean they were
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not clinically significant. For instance, an improvement from a score of 2 to a score of 1 on
the MGS indicates a change from drowsiness or disorientation with variable neurological
deficit, to alertness and orientation with mild clinical or neurological symptoms.
While patients over all scored better on the mRS, GOSE, and MGS at the 4-8 week follow-
up compared to baseline and scores between groups did not differ at either time point, it
would be interesting to see if the patient groups differed on these assessments pre-operatively
when the patients were most symptomatic. In our cohort, most patients were recruited to the
trial after surgery, and therefore prospective evaluations of neurological status using these
scales could not have been made pre-operatively prior to obtaining written informed consent.
The same could be said for the NIHSS. Throughout the study, only one patient had an
NIHSS score greater than one at baseline, and at the 4-8 week follow-up, all patients had a
score of zero. The NIHSS may not be sensitive enough for this patient population in the post-
operative and follow-up period, because many of the functional impairments this scale
detects – such as confusion and disorientation, hemiparesis, dysarthria, and ataxia – are often
resolved after surgery. It may therefore be a more sensitive test in the preoperative period,
when patients are typically at their most symptomatic. One study that used the NIHSS as a
measure of functional improvement in patients with spontaneous ICH found that the test was
reliable and reproducible, but that scores on the assessment needed to change at least 10
points in order for the authors to be confident that a clinically-significant change in
functional status had occurred (Specogna, Patten, Turin, & Hill, 2013). The largest change in
NIHSS from baseline to 4-8 week follow-up in our cohort was by 3-points. Given the
symptoms as well as functional and cognitive limitations experienced by our patients upon
admission, it is possible we would have seen larger changes in NIHSS if follow-up was
compared to a pre-operative assessment.
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5.4.4 QUALITY OF LIFE FROM BASELINE TO FOLLOW-UP
5.4.4.1 SF-36
There was no difference in quality of life score across any of the eight health dimensions
measured by the SF-36 questionnaire both at baseline and the 4-8 week follow-up. As
expected, scores were higher on the 4-8 week follow-up questionnaires than at baseline,
consistent with an improvement in quality of life. Only the control group showed a
statistically significant improvement in scores with respect to role limitations due to physical
health. While there is no published or advised minimum time period required between
questionnaire administration to ensure validity and avoid recall bias, the SF-36 questionnaire
has been validated in other patient populations with good test-retest reliability (Dorman,
Waddell, Slattery, Dennis, & Sandercock, 1997).
5.4.4.2 HUI
Single-attribute scores on the HUI3 and HUI2 did not differ between study groups at follow-
up. Single-attribute utility scores are useful in determining the level of functionality on am
individual health attribute, such as dexterity, pain, or cognition (Feeny et al., 2002).
Mean overall HUI3 and HUI2 multi-attribute HRQL utility scores also did not differ between
groups at 4-8 week follow-up. Within groups, patients in the TXA arm and control arm both
scored higher at the 4-8 week follow-up QOL assessments than at baseline, consistent with
an expected improvement in multi-attribute quality of life. Only the control group showed a
statistically significant improvement in HUI3 and HUI2 HRQL scores from baseline to 4-8
week follow-up. In any case, these improvements would be considered clinically significant.
For instance, at baseline, three patients in the control group and three patients in the TXA
group had an HUI3 HRQL score below zero, indicating an overall multi-attribute health state
worse than death. At follow-up, no patients in either group had an overall HUI3 HRQL score
below zero, a clinically-significant improvement.
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The use of the HUI has been validated in both general and patient populations, including
individuals with diabetes mellitus, dementia, arthritis, or who have suffered a severe trauma
(Kavirajan, Hays, Vassar, & Vickrey, 2009; Khanna et al., 2011; Mo, Morrison, Choi, &
Vardy, 2006; Ringburg et al., 2011). To our knowledge, ours is the first study to use the HUI
as a QOL assessment tool in CSDH patients. Still, future studies would be needed to further
assess the construct validity of the HUI questionnaire in this patient population.
A study that compared the discriminative ability of the HUI3 to the SF-36 preference-based
SF-6D assessment in chronic kidney disease patients found the HUI3 to be better able to
discriminate depressive symptoms, and better suited in patients with greater disability that
the general population (Davison, Jhangri, & Feeny, 2009). One study found the HUI3 in
particular to be most sensitive in assessing health-related QOL resulting from older age
(great than 65-years old) and comorbidity (Polinder et al., 2010). They also found that the
HUI3 and HUI2 had greater discriminative ability and was more informative than other HR-
QOL assessment tools for a number of diseases, including skull-brain injury.
The HUI questionnaire in particular was a very sensitive tool for assessing the degree to
which important health attributes are affected. Impairments on the functional domains
assessed by the HUI3 and HUI2 levels were often consistent with the presenting symptoms
caused by the mass effect of a subdural hematoma. For instance, pain levels at baseline
consistent with the headaches patients reported upon admission. However, it is also
important to note that many of the health levels measured by this questionnaire are already
impaired in senior populations as a function of old age, including vision, dexterity,
ambulation, and cognition. The objective improvement in scores from baseline to follow-up
does however suggest that the CSDH did contribute to impairment across these health
attributes.
It is also interesting to note that according to HUI HRQL score classifications into disability
categories, no patients reached perfect health across all attributes at the 4-8 week follow-up.
This has potentially important clinical implications – while neurosurgical follow-up and
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intervention is often not required after 4-8 weeks, patients may still benefit from some form
of clinical follow-up.
5.4.5 TXA SAFETY: ADVERSE EVENTS AND SAFETY OF TXA
DOSING REGIMEN
There was no significant difference in number of adverse events experienced by patients in
the TXA treatment arm compared to the control arm. We acknowledge however that this
does not translate to equivalent safety among the groups. A larger clinical trial would be
needed to distinguish whether or not TXA significantly increases the risk of certain AEs
compared to control patients. A larger sample size in the full trial may see the occurrence of
more serious adverse events, and potentially a difference between the two groups.
There were no mortalities in our study cohort, and no intra-operative or post-operative
complications. There were no AEs associated with abnormal laboratory test results, including
blood-work or urinalysis.
There were also no occurrences of thromboembolic events in our study cohort. Several times
over the past few decades, the notion that TXA increases the risk of thromboembolic events
has resurfaced, despite much evidence against it. While our study is too small to draw a
conclusion from this finding with regards to the risk of thromboembolic events from TXA,
this finding does support the large-scale research refuting this claim. Many studies have
refuted this claim, showing in controlled studies that TXA does not increase the risk of
thromboembolic events. Studies with higher daily dosing regimens than our 1500 mg daily
dose have also not reported any thromboembolic events in their patients (Lukes et al., 2010).
Larger-scale trials of the safety of TXA in heavy menstrual bleeding also found that TXA
does not increase the risk of thromboembolic events with thromboembolism rates even
comparable to that of the general population (Lukes, Freeman, Van Drie, Baker, &
Adomako, 2011).
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Another concern related to TXA treatment is ophthalmic changes, including new visual
acuity deficits, retinal vein occlusion, and sudden chromatopsia. These events have been
rarely reported in the post-marketing period, particularly in higher and longer-duration
dosing regimens, and have therefore been highlighted as a concern in the TXA product
monograph. No patients in our cohort experienced vision-related AEs, including new visual
deficits or any self-reported changes in colour vision. In a study investigating the efficacy
and safety of a daily TXA dosing regimen in patients with menorrhagia, taken for five days
over nine menstrual cycles, the authors reported no ophthalmic AEs related to colour vision
(Lukes et al., 2010). However, there was one case of high intraocular pressure, two
occurrences of blurred vision in the same patient, and one case of retinal artery stenosis. It is
important to note however that the mean daily dose of oral TXA in this study was 3800 mg
for an average of 3.5 days per cycle – more than twice that of our trial. It is possible then that
our dosing regimen is not high enough to substantially increase the risk of ophthalmic-related
AEs, supporting the safety of our chosen dosing regimen.
Overall, there were 33 occurrences of 18 different adverse events, none of which were
serious and unexpected. These numbers, along with the insignificant difference in number of
AEs between treatment groups, suggest that the TXA dosing regimen is safe for this patient
population.
Most adverse events were experienced in the acute post-operative period and resolved within
a couple of days. The most frequently reported adverse event was headache. This is a
potential side-effect of TXA and was therefore an expected adverse event. However,
headache is experienced by nearly if not all neurosurgery patients in the acute post-operative
period, so this adverse event is more likely attributable to neurosurgical intervention than the
study drug. Moreover, in our study cohort, there was no statistically significant difference in
headaches experienced by patients in the control group compared to the TXA group,
supporting the fact that TXA use did not increase the occurrence of headaches. In fact, more
patients in the control group reported headache compared to the TXA group, though this may
be related to the fact that more patients in the control group presented with headache upon
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admission. It is possible that our TXA dose was not high enough to significantly increase the
risk of headache, thereby supporting the safety of our selected study drug dose regimen.
Most other adverse events experienced were also common post-operative risks, such as post-
operative dysphagia, for which many patients are referred to rehabilitation centers for days to
weeks after surgery to aid in recovery. Two patients (8%) experienced nausea or stomach
upset, which is a potential side-effect of TXA, but also a common occurrence post-
anesthesia.
Overall there were four occurrences of GI-related AEs, and no significant differences
between the two groups. Two patients in the control group experienced stomach pain, and
two patients – one in the control group and the other in the TXA group – experienced nausea
or stomach upset. These events were graded by the PI as mild in severity, and are consistent
with the literature, where most GI-related events are mild or moderate in severity (Lukes et
al., 2010). These were not considered by the PI to be likely related to the study drug.
It is important to clarify that many reported adverse events related to TXA are also common
post-operative side effects, either with relation to the procedure or the exposure to a general
anesthetic. Therefore, it is difficult to distinguish study-related adverse events from surgical
side effects.
The most serious adverse event experienced was seizure, reported by one study patient in the
TXA treatment arm. Seizures have been associated with TXA treatment, possibly due to a
mechanism involving the inhibitory neurotransmitter GABA. While the risk of seizure from
TXA is still being investigated, it is likely dose related, with the risk of seizure increasing
with increasing dose (Schwinn, Mackensen, & Brown, 2012). Regarding the patient in our
cohort who experienced a seizure within two days of hematoma evacuation, it is also
possible the occurrence of a seizure was more likely related to another of the patient’s
concomitant medication with higher seizure risk than TXA, or possibly due to the post-
operative risk of seizure related to burr-hole procedures. Aging and cognitive impairment
also predisposes an individual to seizures. In any case, it is plausible that the seizure was
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related to TXA, and this correlation cannot be excluded. The literature does consider seizures
as a major AE related to TXA treatment and is therefore a risk that should continue to be
disclosed to patients during the consent procedure. Additionally, patients with a history of a
seizure disorder should not be eligible in investigational trials until more safety-related
evidence with respect to the risk of seizures is accumulated.
5.5 STUDY LIMITATIONS
Our study is not without limitation. The largest study limitation we faced was a small sample
size. According to our sample size calculation, which was based off of previous literature
investigating CSDH volume change after TXA treatment, we needed at least 46 participants
to detect a statistically significant treatment effect. Therefore, our study cohort of 24 patients
was likely too small to sufficiently power the study for this outcome measure. However, the
sample size was still sufficient to evaluate the feasibility of conducting this trial at our
institution.
We made substantial effort to improve the recruitment rate, through quality improvement
initiatives, modification of eligibility criteria, and regular oversight by the study team.
We did see some improvement in recruitment, particularly after modifying eligibility criteria,
however overall there was still a decreasing trend in overall recruitment rate over time. In
future studies, we should do our best to organize regular meetings with key study
stakeholders, including the study PI and co-investigators, to report on recruitment rate and
study progress.
Another limitation is the limited number of patients who returned for the second follow-up
visit. Patients were often informed by their attending physician that clinically and
radiologically, they no longer required follow-up and were therefore cleared from
neurosurgical care. This discouraged study participants from wanting to return for the second
follow-up, as it was no longer clinically needed according to the attending neurosurgeon.
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Further, there was missing data across several outcome measures in our study. Most
importantly, the baseline CT scans for two patients were performed at outside institutions
from which the patients were subsequently transferred to St. Michael’s Hospital for subdural
hematoma management. We are still in the process of trying to obtain those baseline images.
As discussed above, another limitation is the standardization of the CT images. Despite ours
and the imaging departments best efforts to standardize the CT scanner used for subdural
hematoma patients, not all patients had their post-operative and follow-up CT scans in the
GE Revolution scanner. Therefore, there was not a uniform CT thin-slice thickness across all
images – while most CT scans were 2.5 mm thin-slices, others were either 1.25 mm, 1.63
mm, or 5 mm. This may have affected the standardization of the hematoma volume
measurement technique.
While manual delineation of CSDH area on each slice is considered the ‘gold standard’ for
volume measurement, it is quite time-intensive. Moreover, a possible limitation of this
volume measurement technique arises when measuring an isodense hematoma. By definition,
these hematomas are the same density as the surrounding brain tissue, making their borders
difficult to delineate even when adjusting the brightness and contrast of the image.
Therefore, the CSDH measurements may be subjective as the hematomas borders are at the
discretion of the blinded assessor. Potential solutions include consultation with a second
viewer when the margins are difficult to see, or having two independent blinded assessors
each measure all of the hematoma volumes, and calculating an inter-rater reliability score to
validate the objectivity and accuracy of this measurement technique.
With regards to our statistical analysis plan, multiple testing increases the risk of Type I error
– that is, falsely rejecting the null hypothesis. This Type I error “inflation” results from
multiple comparisons sharing control, or baseline, data. Caution must therefore be taken with
the interpretation of these study results. It is possible and often recommended to statistically
correct for the effects of multiple hypothesis testing. However, the literature is not
conclusive as to whether or not post-hoc correction for multiple testing should always be
carried out in clinical trials, and there is definitely a need for standardized guidelines with
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respect to this issue (Howard, Brown, Todd, & Gregory, 2018; Wason, Stecher, & Mander,
2014). After running the post-hoc Benjamini-Hochberg correction on our results, controlling
the false discovery rate at 5%, no results remained statistically significant. Ideally, when
planning a clinical trial, minimizing the number of variables and using composite endpoints
will reduce the degree of multiplicity in statistical analyses.
Many of the measured outcomes are also analyzed in terms of change, namely, the change in
hematoma volume from baseline to follow-up. These statistical tests comparing units of
change however are not sufficiently powerful analyses for a clinical trial, as they are subject
to regression artifact. The future main trial will be designed so that the follow-up measures
are analyzed with the baseline values as covariates, using Analysis of Covariance
(ANCOVA) as the statistical testing method.
A larger, multi-centre pilot trial would have been beneficial to inform feasibility issues more
broadly across different centres, helping in the implementation of a larger multicenter RCT.
Due to limited study funding and personnel, it would have been difficult to conduct the trial
across several sites.
Despite the fact that the trial had an open-label design, we did make an effort to blind study
outcomes. For instance, all CT scans were anonymized and only linkable to treatment arm
through a master linking log. All neurological assessments and QOL measures were only
identifiable through a linking log connecting the anonymized patient study ID to the patient’s
name. Despite these efforts, complete blinding was unfortunately not possible, especially
because the same study coordinator to enroll patients was also the one to collect outcome
measures including for instance administering QOL assessments. For the main trial, which
will be placebo-controlled, these assessments will all be completely blinded as not even the
research coordinator will be privy to study assignment.
Further, we acknowledge that we did not define thresholds or metrics for our feasibility
measures, which are needed to objectively determine whether the pilot trial sufficiently
demonstrates study feasibility. This is particularly important because we did not meet our
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intended sample size recruitment. In the future main trial, we will define specific feasibility
metrics, including recruitment rates over a pre-specified study duration, attrition rates, and
eligibility rates.
Finally, it is important to recognize the potential dangers of reporting efficacy measures
when conducting a feasibility trial, especially if the target sample size is not reached as in our
pilot trial. Reporting efficacy results could mislead readers because of Type I or Type II
errors from underpowered analyses, and sample sizes in pilot feasibility trials are never
sufficient to power measures of efficacy.
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6. CONCLUSIONS
In conclusion, we have demonstrated the feasibility and safety of a trial investigating TXA in
patients with residual CSDH after surgical evacuation.
While the results were not statistically significant, there was a trend towards a greater
hematoma volume reduction in TXA-treated participants compared to control participants.
There was no difference between groups in hematoma recurrence and reoperation rate, with
two patients in each treatment group experiencing accumulation of their hematomas that
required another surgical evacuation. Overall, there was a trend towards improvement in
neurological status and QOL from baseline to 4-8 week follow-up in both TXA-treated and
control subjects, with control subjects showing a statistically-significant improvement in
QOL in the ‘role limitations due to physical health’ category on the SF-36 questionnaire and
in the HUI3 multi-attribute HRQL utility score. There were no significant difference in AE
occurrences between study groups and all AEs were mild or moderate in nature. There were
no cases of thromboembolic events. There were no or reported or measured ophthalmic
changes in either retinal integrity, colour vision, or visual acuity.
The results of this study will inform the conduct of a future, double-blind, randomized
controlled trial investigating the efficacy of TXA therapy in residual CSDH and its potential
to prevent post-operative CSDH recurrence.
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7. FUTURE DIRECTIONS
7.1 DOUBLE-BLINDED EFFICACY TRIAL
The primary outcome of this pilot trial was to determine the feasibility of such a study, and
therefore the potential of running a larger, multi-centre double-blind randomized controlled
trial. The primary outcome of this future trial would be to assess the efficacy of TXA in
residual CSDH resolution, and in preventing hematoma recurrence.
We have shown that such a study is feasible. Further, with the preliminary radiological data
from this pilot, we can re-calculate the sample size needed to power a future trial using the
change in hematoma volumes of the patients in our cohort, rather than relying solely on
values in the literature.
Therefore, based on our experiences with this pilot study, we are now in the stages of
initiating a double-blinded, placebo-controlled randomized controlled trial (TRACE-2).
TRACE-2 will differ from this pilot investigation in several ways. First, it will be double-
blind and placebo-controlled. This is particularly important to mitigate the potential for
placebo effect with respect to the secondary QOL measures.
Second, the first dose of TXA will be an intraoperative 1g-loading dose (all subsequent doses
will be in the form of 500 mg oral tablets, following the same dosing regimen as our pilot).
As a result, participant recruitment and informed-consent will necessarily take place pre-
operatively. This protocol change will allow us to collect preoperative baseline clinical data,
including MGS and NIHSS at baseline.
Do date, we have received Health Canada approval to conduct this study, secured grant
funding, and finalized a contract with the Bay Area Research Logistics (BARL), a
pharmacological company that will provide matching placebo.
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Finally, based on the safety data of our pilot trial, we are modifying the exclusion criteria to
increase the proportion of CSDH patients that are eligible for TRACE-2. One criterion in
particular is in relation to thrombotic events. No patients in our pilot study experienced a
thromboembolic event, consistent with other larger reports in the literature.
Following this trial, depending on whether future trial results support the use of TXA as an
adjunct to surgical treatment of CSDH, our long-term goal would be to carry out an efficacy
trial in conservatively-managed CSDH patients, and see whether TXA could be used as an
alternative treatment for patients who might otherwise not be good surgical candidates.
7.2 SCOPING REVIEW OF CSDH PATHOGENESIS
To further a more comprehensive understanding of subdural hematoma pathogenesis, we
undertook a comprehensive systematic scoping review of primary literature in an attempt to
elucidate 1) the temporal ordering of pathogenic processes involved in CSDH development,
and 2) potential biomarkers as predictors of recurrence.
We conducted the literature search and review according to Arksey and O’Malley’s
methodological framework for scoping reviews to synthesize the current literature regarding
pathophysiology of CSDH (Arksey & O’Malley, 2005; Levac, Colquhoun, & O’Brien,
2010). In comparison to a systematic review which asks a research question about the
effectiveness of an intervention, a scoping review asks a broad question to synthesize
existing knowledge pertaining to a particular field. We therefore elected to conduct a
systematic scoping review because of the broad nature of the question of interest, intended to
provide a comprehensive synthesis of the current knowledge as well as highlight the gaps in
the literature regarding CSDH pathogenesis; the variety of hypotheses tested (i.e.
angiogenesis, inflammation, etc.) and methodologies employed (i.e. immunohistochemistry,
enzyme-linked immunosorbent assay (ELISA), etc.) by the studies included in the review;
and the unavailability of research quality appraisal tools for exploratory studies of this
nature.
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We performed a systematic search of five electronic databases (Medline, PubMed,
EMBASE, Web of Science, and Cochrane) from their time of inception to July 2017. The
search was conducting according to the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines using search terms comprised of keywords and
medical subject heading (MeSH) terms encompassing CSDH and pathophysiology (Moher,
Liberati, Tetzlaff, Altman, & Altman, 2009). We also consulted an experienced information
specialist to assure accuracy and comprehensiveness of the search.
We screened all article titles and abstracts against predetermined eligibility criteria. We
included peer-reviewed primary literature investigating CSDH membrane and fluid
histopathology, morphology, genetic profile, expression profiles, and molecular, cellular, and
metabolic markers and pathways, using either microscopy, immunohistochemistry, ELISA,
Western blots, or other validated laboratory technique. We excluded non-English articles,
reviews, letters, conference papers or abstracts, case reports, and studies based on animal
models. After arriving at the articles to be included in our review, we extracted data from
each paper according to pre-defined data collection variables. These variables included
sample demographics (number of participants, number of samples, country, age,
comorbidities, history of trauma), study hypothesis and objective, imaging data,
methodology, findings and conclusions. Our paper search and screening process, conducted
according to PRISMA, is presented in Figure 16.
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Figure 16. PRISMA Flowchart. Systematic search process and results according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines
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We are currently still in the process of data extraction and compiling the results, and will
present the results thematically based on predominant underlying mechanism explored in
each paper.
7.3 DEVELOPING A PROGNOSTIC MODEL TO ESTIMATE RISK OF CSDH
RECURRENCE
Identifying predictors of recurrence would be instrumental to the current neurosurgical care
of subdural hematoma patients. Stanisic et al. (Stanišić & Pripp, 2017) and Jack et al. (Jack,
O’Kelly, McDougall, & Max Findlay, 2015) created grading systems for predicting
recurrence requiring reoperation. However, these prognostic models included only radiologic
hematoma features as factors that could significantly predict recurrence. Despite these
systems, a comprehensive model – one that can integrate clinical, demographic, operative,
and radiographic factors into a predictive model – is lacking. We believe that a machine-
learning algorithm capable of estimating recurrence risk based on the presence or absence of
a variety of clinical factors would be able to achieve this. We understand that a substantially
larger sample size would be required in order to produce an algorithm that is both internally
and externally validated.
We will retrospectively review the cases of all subdural hematoma patients consecutively-
admitted to St. Michael’s Hospital within the past decade, and collect demographic, clinical,
radiologic, and surgical factors as pre-operative and post-operative predictors of hematoma
recurrence. This data will also be useful for identifying predictors of overall health outcome.
We will use this comprehensive dataset to develop a machine-learning algorithm that will
incorporate clinical, demographic, operative, and radiographic factors into a prognostic
grading system for predicting risk of hematoma recurrence. To test, develop, and validate the
machine-learning algorithm, we will use the PythonTM programming language and
MATLAB® programming software.
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7.4 INVESTIGATING CSDH PATHOGENESIS
In this study we categorized the subdural hematoma subtypes according to a classification
system proposed by Alves et al. (Alves, Santiago, Costa, & Pinto, 2016). These
classifications are based on radiologic imaging. Further research is needed to understand the
pathophysiology and characteristics underlying each subdural hematoma subtype, and how
the histology and molecular pathology correlates to radiologic subtypes. This could also help
elucidate the mechanism of CSDH pathogenesis, which would be helpful in determining
causative factors for post-operative recurrence.
Thus far we have focused on hyperfibrinolysis, however, as the literature suggests, CSDH
progression is likely multifactorial. We are therefore curious to explore other potential
mechanisms involved in hematoma development and recurrence, such as angiogenesis. For
instance, re-bleeding from the hematoma’s outer membrane may contribute to the acute
bleeds within these hematomas. A possible explanation is that higher levels of angiogenesis
in the outer membrane increase the amount of re-bleeding into the CSDH, which then
increases the risk of recurrence and therefore the need for re-operation. While measures of
VEGF in hematoma fluid have supported the theory that angiogenesis is occurring in
CSDHs, we believe that quantifying angiogenesis in the hematoma could more specifically
elucidate the extent to which it plays a role in CSDH pathogenesis.
Cluster of differentiation 31 protein (CD31) (also known as Platelet endothelial cell adhesion
molecule (PECAM-1)) is a highly-specific protein marker for endothelial cells. It has a
significant role in endothelial cell interactions during angiogenesis (Escosa Baé, Wessling,
Salca, & de las Heras Echeverría, 2011). This marker is used in immunohistochemical
preparations to quantify angiogenesis and neovascularization in a tissue sample (Wang et al.,
2008). To our knowledge, it has not been used previously to quantify angiogenesis in the
outer membrane of CSDH. This may allow us to develop a classification system that
correlates degree of angiogenesis with risk of recurrence.
120
We therefore propose a study where we will classify chronic subdural hematomas into
subtypes based on the degree of angiogenesis measured immunohistochemically with CD31
staining, and with immunoassays specific for VEGF. To our knowledge this would be the
first study to quantify angiogenesis in the outer membrane in relation to a hematoma-type
classification system.
The primary objective of this study is to investigate and elucidate the pathophysiological
mechanism underlying CSDH development and enlargement, and study potential
histopathological risk factors for post-operative recurrence.
We propose quantifying angiogenesis in the outer membrane by determining the mean
microvessel density (MVD) with CD31 immunohistochemical staining. Mean MVD per unit
area and intensity scores will be determined from these preparations. We will also measure
VEGF levels in the hematoma outer membrane, hematoma fluid, and systemic serum.
Because CD31 has not previously been used to quantify angiogenesis in hematoma
membrane tissue, we will compare angiogenesis levels as quantified by CD31 staining to
VEGF levels in the outer membrane and hematoma fluid, as VEGF has been used as a
marker to indicate angiogenesis in CSDH in previous literature, thereby also aiming to
validate the use of CD31 staining in CSDH.
We will use ELISA to measure VEGF expression (concentration in pg/mL) in samples of the
hematoma outer membrane, the hematoma fluid, and systemic serum. We will obtain
commercially-available ELISA kits to carry out the assays. We will also use ELISA to
measure levels of pro-inflammatory (IL-6, IL-8, TNF-alpha) and anti-inflammatory
cytokines (IL-10) in hematoma fluid, which have previously been identified in CSDH.
Levels of pro- and anti-inflammatory cytokines will be correlated to levels of VEGF and
angiogenesis as quantified with CD31 staining.
Secondarily we will also study the cytoarchitecture of the outer hematoma membrane,
elucidating some of the inflammatory processes underlying CSDH development such as
eosinophilic infiltration. To do so, histological slides of hematoma outer membrane samples
121
will be prepared with standard hematoxylin and eosin (H&E) staining techniques. We will
use light microscopy to perform inflammatory (eosinophil) cell counts as a measure of
eosinophilic infiltration and inflammation in the outer membrane, as well as study the
general cellular architecture of the outer membrane.
We hypothesize that the degree of angiogenesis – as measured by mean microvessel density
(MVD) – will be highest in the outer membranes of hematoma subtypes with acute
components and loculations and septations, as seen on CT imaging. Concurrently we also
hypothesize higher VEGF concentrations in the hematoma fluid of these subtypes compared
to the other hematoma types. We expect higher post-operative recurrence rates in patients
with these hematoma subtypes.
We have already begun collecting hematoma samples, including hematoma fluid, the inner
membrane, and outer membrane, which are collected from patients at the time of surgery by
the treating surgical team, and stored in a brain tissue biobank in a nitrogen freezer.
Results from this study would provide insight into the pathologies underlying CSDH
development, enlargement, and recurrence. Elucidating inflammatory and angiogenic
biomarkers of CSDH pathogenesis could inform the currently unknown mechanism of
CSDH pathogenesis, potentially exposing specific targets for medicinal interventions that
could be personalized for patients with certain CSDH radiographic subtypes. For example, if
higher angiogenesis is observed in hematoma types that have previously been suggested to
be more likely to recur, medicinal interventions targeting angiogenesis could be provided for
those patients. Future studies could investigate the use of antiangiogenic medications in
CSDH patients, such as bevacizumab (a monoclonal antibody that binds to VEGF,
preventing it from acting at its receptor site), which is currently used in certain cancer types
and age-related macular degeneration.
120
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APPENDIX A: Glasgow Coma Scale
Eye Opening (E) 4 = spontaneous 3 = to voice 2 = to pain 1 = none Verbal Response (V) 5 = normal conversation 4 = disoriented conversation 3 = words, but not coherent 2 = no words, only sounds 1 = none Motor Response (M) 6 = normal 5 = localized to pain 4 = withdraws to pain 3 = decorticate posture (an abnormal posture that can include rigidity, clenched fists, legs held straight out, and arms bent inward toward the body with the wrists and fingers bend and held on the chest) 2 = decerebrate (an abnormal posture that can include rigidity, arms and legs held straight out, toes pointed downward, head and neck arched backwards) 1 = none
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APPENDIX B: Glasgow Coma Scale-Extended
1 Death D 2 Vegetative state VS 3 Lower severe disability SD - 4 Upper severe disability SD + 5 Lower moderate disability MD - 6 Upper moderate disability MD + 7 Lower good recovery GR - 8 Upper good recovery GR +
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APPENDIX C: Markwalder Grading Score
Score Description 0 Neurologically normal 1 Alert and orientated: absence of mild symptoms such as headache, or mild
neurological deficit such as reflex asymmetry 2 Drowsy or disorientated, or variable neurological deficit such as hemiparesis 3 Stuporous, but responding appropriately to noxious stimuli, several focal
signs such as hemiplegia 4 Comatose with absent motor responses to painful stimuli, decerebrate or
decorticate posturing
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140
APPENDIX D: modified Rankin Scale
Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties
and activities 2 Slight disability; unable to carry out all previous activities, but able to look
after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to
attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care
and attention 6 Dead
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https://doi.org/10.1177/003693305700200401
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APPENDIX E
HUI Mark 3 (HUI3) Classification System
ATTRIBUTE LEVEL DESCRIPTION
VISION 1 Able to see well enough to read ordinary newsprint and recognize a friend on the other side of the street, without glasses or contact lenses.
2 Able to see well enough to read ordinary newsprint and recognize a friend on the other side of the street, but with glasses.
3 Able to read ordinary newsprint with or without glasses but unable to recognize a friend on the other side of the street, even with glasses.
4 Able to recognize a friend on the other side of the street with or without glasses but unable to read ordinary newsprint, even with glasses.
5 Unable to read ordinary newsprint and unable to recognize a friend on the other side of the street, even with glasses.
6 Unable to see at all.
HEARING 1 Able to hear what is said in a group conversation with at least three other people, without a hearing aid.
2 Able to hear what is said in a conversation with one other person in a quiet room without a hearing aid, but requires a hearing aid to hear what is said in a group conversation with at least three other people.
3 Able to hear what is said in a conversation with one other person in a quiet room with a hearing aid, and able to hear what is said in a group conversation with at least three other people, with a hearing aid.
4 Able to hear what is said in a conversation with one other person in a quiet room, without a hearing aid, but unable to hear what is said in a group conversation with at least three other people even with a hearing aid.
5 Able to hear what is said in a conversation with one other person in a quiet room with a hearing aid, but unable to hear what is said in a group conversation with at least three other people even with a hearing aid.
6 Unable to hear at all.
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SPEECH 1 Able to be understood completely when speaking with strangers or friends.
2 Able to be understood partially when speaking with strangers but able to be understood completely when speaking with people who know me well.
3 Able to be understood partially when speaking with strangers or people who know me well.
4 Unable to be understood when speaking with strangers but able to be understood partially by people who know me well.
5 Unable to be understood when speaking to other people (or unable to speak at all).
AMBULATION 1 Able to walk around the neighbourhood without difficulty, and without walking equipment.
2 Able to walk around the neighbourhood with difficulty; but does not require walking equipment or the help of another person.
3 Able to walk around the neighbourhood with walking equipment, but without the help of another person.
4 Able to walk only short distances with walking equipment, and requires a wheelchair to get around the neighbourhood.
5 Unable to walk alone, even with walking equipment. Able to walk short distances with the help of another person, and requires a wheelchair to get around the neighbourhood.
6 Cannot walk at all.
DEXTERITY 1 Full use of two hands and ten fingers.
2 Limitations in the use of hands or fingers, but does not require special tools or help of another person.
3 Limitations in the use of hands or fingers, is independent with use of special tools (does not require the help of another person).
4 Limitations in the use of hands or fingers, requires the help of another person for some tasks (not independent even with use of special tools).
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5 Limitations in use of hands or fingers, requires the help of another person for most tasks (not independent even with use of special tools).
6 Limitations in use of hands or fingers, requires the help of another person for all tasks (not independent even with use of special tools).
EMOTION 1 Happy and interested in life.
2 Somewhat happy.
3 Somewhat unhappy.
4 Very unhappy.
5 So unhappy that life is not worthwhile.
COGNITION 1 Able to remember most things, think clearly and solve day to day problems.
2 Able to remember most things, but have a little difficulty when trying to think and solve day to day problems.
3 Somewhat forgetful, but able to think clearly and solve day to day problems.
4 Somewhat forgetful, and have a little difficulty when trying to think or solve day to day problems.
5 Very forgetful, and have great difficulty when trying to think or solve day to day problems.
6 Unable to remember anything at all, and unable to think or solve day to day problems.
PAIN 1 Free of pain and discomfort.
2 Mild to moderate pain that prevents no activities.
3 Moderate pain that prevents a few activities.
4 Moderate to severe pain that prevents some activities.
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5 Severe pain that prevents most activities.
HUI Mark 2 (HUI2) Classification System.
ATTRIBUTE LEVEL DESCRIPTION
SENSATION 1 Able to see, hear, and speak normally for age.
2 Requires equipment to see or hear or speak.
3 Sees, hears, or speaks with limitations even with equipment.
4 Blind, deaf, or mute.
MOBILITY 1 Able to walk, bend, lift, jump, and run normally for age.
2 Walks, bends, lifts, jumps, or runs with some limitations but does not require help.
3 Requires mechanical equipment (such as canes, crutches, braces, or wheelchair) to walk or get around independently
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4 Requires the help of another person to walk or get around and requires mechanical equipment as well.
5 Unable to control or use arms and legs.
EMOTION 1 Generally happy and free from worry.
2 Occasionally fretful, angry, irritable, anxious, depressed, or suffering night terrors
3 Often fretful, angry, irritable, anxious, depressed, or suffering night terrors
4 Almost always fretful, angry, irritable, anxious, depressed.
5 Extremely fretful, angry, irritable, anxious, or depressed usually requiring hospitalization or psychiatric institutional care.
COGNITION 1 Learns and remembers school work normally for age.
2 Learns and remembers school work more slowly than classmates as judged by parents and/or teachers.
3 Learns and remembers very slowly and usually requires special educational assistance.
4 Unable to learn and remember.
SELF-CARE 1 Eats, bathes, dresses, and uses the toilet normally for age.
2 Eats, bathes, dresses, or uses the toilet independently with difficulty.
3 Requires mechanical equipment to eat, bathe, dress, or use the toilet independently.
4 Requires the help of another person to eat, bathe, dress, or use the toilet.
PAIN 1 Free of pain and discomfort.
2 Occasional pain. Discomfort relieved by non-prescription drugs or self-control activity without disruption of normal activities.
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3 Frequent pain. Discomfort relieved by oral medicines with occasional disruption of normal activities.
4 Frequent pain; frequent disruption of normal activities. Discomfort requires prescription narcotics for relief.
5 Severe pain. Pain not relieved by drugs and constantly disrupts normal activities.
FERTILITY 1 Able to have children with a fertile spouse.
2 Difficulty in having children with a fertile spouse.
3 Unable to have children with a fertile spouse.
Horsman, J., Furlong, W., Feeny, D., & Torrance, G. (2003). The Health Utilities Index (HUI):
concepts, measurement properties and applications. Health and Quality of Life
Outcomes, 1, 54. https://doi.org/10.1186/1477-7525-1-54