CSDH-Trial RESEARCH PROTOCOL v-23-5-05 1€¦ · demonstrated on a CT scan within six months of the original drainage procedure which is judged by the admitting consultant surgeon

Cambridge Chronic Subdural Haematoma Trial Protocol (04/Q0108/52) - Version 23/5/05

RESEARCH PROTOCOL

Cambridge Chronic Subdural Haematoma Trial [Trial of treatment of chronic subdural haematoma

with or without external drainage]

REC No 04/Q0108/52

Principal investigator: Mr Peter J Hutchinson

Investigators: Thomas Santarius, Peter J Kirkpartick, Dharmendra Ganesan, Hui

Ling Chia, Ibrahim Jalloh, Hani Marcus, Hugh Richards*

*Trial Statistician

Trial sponsors: Addenbrooke’s Hospital NHS Trust

University of Cambridge

Contents 1. Abstract

2. Introduction 3. Hypotheses 4. The proposed trial 5. Research subjects 6. Consent 7. Randomisation and blinding 8. Outcome measures 9. Power 10. Clinical protocol 11. Data management 12. Ethical approval 13. Indemnity arrangements 14. Publication 15. References 16. Appendices (Research Protocol Flowchart, Consent Algorithm, Consent

Form, Admission Proforma, Discharge Proforma, Operation Protocol, Follow

up Proforma)


1. Abstract

The Cambridge Chronic Subdural Haematoma Trial is a prospective randomised control trial of the use of subdural-to-external closed drains after burr hole evacuation

of chronic subdural haematoma in adult patients. Eligible patients will be randomly allocated to drain or no-drain treatment arms. The primary outcome is recurrence rate.

The secondary outcomes are mortality at 30 days and six months, functional status at discharge (GCS, MRS and the presence of gross neurological) and six months (MRS,

the presence of gross neurological deficit, mobility and type of accommodation required), the duration of neurosurgical hospital stay and the presence of

neurosurgical complications. In total 400 patients will be recruited (power 0.8, p =

0.05).

2. Introduction Chronic subdural haematoma is a common condition primarily affecting the elderly1.

It is a cause of major morbidity and mortality, yet it is treatable by relatively simple techniques and the majority of patients improve rapidly following surgical

intervention. The incidence of CSDH in those aged over 70 years is 58 per 100,000 per year compared to 3.4 per 100,000 per year in those under 652. As the proportion

of people aged 65 and over is expected to double worldwide between years 2000 and 20303, a considerable rise in the incidence of CSDH is to be expected.

CSDH arises in the layer of loose dural border cells, an innermost layer of dura

surrounded by firmly adherent dura cells on one side and arachnoid cells on the other 4. Traversing veins, firmly anchored at their pial and dural ends, are being

increasingly stretched by the shrinking brain until enough momentum can be

generated by only a small force to cause rupture through stretching or shearing. The

mechanisms behind the maintenance of the chronic state of CSDH are still poorly

understood, but in essence, the subdural space is not well equipped to reabsorb the ensuing haematoma.

Currently, three techniques are most commonly employed in the treatment of CSDH:

twist drill craniostomy (less than 5mm in diameter), burr hole craniostomy (5-30mm

in diameter) and craniotomy5. A meta-analysis by Weigel et al showed that all three

techniques have approximately the same mortality (2–4%)5. Craniotomy is associated

with a significantly higher morbidity (12 % versus 4% for craniostomies) and twist

drill craniostomy has significantly higher recurrence rate (33% versus 12% and 11%

for burr hole craniostomy and craniotomy). Not surprisingly, burr hole craniostomy,

an evacuation via one or two burr holes drilled over the site of the haematoma, is the

most popular surgical technique world-wide5-7

.

The recurrence of CSDH after the initial drainage procedure ranges from

approximately 5 to 30%5. Re-operation carries the peri-operative risks associated with

a second operation. Therefore, developing management strategies that are practical,


safe and carry minimal risk of recurrence has been the focus of clinical research in

CSDH. The central issue in the debate about minimising the recurrence rate is

whether post-operative drainage should be used in conjunction with burr hole

craniostomy7. Since Laumer’s prospective study

8, when no difference was found

between recurrences in patients with and without post-operative drainage, there has

been a growing body of evidence suggesting that post-operative drainage of the

subdural space is associated with significantly lower recurrence rates 6;9;10

.

Although being prospective and randomised, the studies by Wakai et al and Tsustumi et al were not formal controlled trials and as such are open to a range of bias. The

need for Class I evidence to guide the treatment of CSDH has been repeatedly recognised and called for5;7;11. The aim of this study is to provide Class I evidence for

the role of the postoperative drainage in the management of CSDH treated with burr hole evacuation.

3. Hypotheses

The principle research question The use of drains following burr hole evacuation of CSDH is associated with lower

recurrence rate.

Secondary research questions The use of drains is associated with better clinical outcome at discharge and six month

follow up [mortality and Modified Rankin Scale (MRS)], and shorter time to discharge from the neurosurgical unit.

4. The proposed trial

The study will be a randomised controlled trial of the use of drains versus no drains

after burr hole evacuation of CSDH.

The target study group will be patients requiring burr hole drainage of CSDH. Apart

from random allocation of treatment with drain or no drain the overall management of

the trial subjects will not differ from the current management of patients with CSDH.

5. Research subjects

Patients referred to our unit for treatment of their CSDH will be screened against the inclusion and exclusion criteria. Suitable patients will be offered participation in the

trial.


Inclusion criteria Patients with CSDH requiring surgical treatment referred to the Neurosurgical

Department of the Addenbrooke's Hospital, Cambridge.

Exclusion criteria Patients younger than 18 years of age.

Patients with CSDH requiring surgical treatment other than burr hole evacuation, e.g. craniotomy.

Patients who underwent an operation for drainage of an ipsilateral CSDH within six months prior to the last admission.

Patients with CSF shunt in-situ. It is judged unsafe (preoperatively) to insert a drain. For example, if there is not

enough room in the subdural space.

Patient will be enrolled as a new subject (and given a new study number) if he/she has

never had an operation for CSDH on ipsilateral side or if such an operation took place

more than six months ago. Bilateral CSDH will be treated as “one study subject” and

each side will receive the same treatment as determined through the randomisation

process.

6. Consent The consent from patient or assent from relatives (in case the patient is unable to give

consent) will be obtained by the surgeon performing the operation. All surgeons in the department will be familiar with the research protocol. Consent will be obtained

during discussion of the patient’s condition and the treatment options. Subjects can withdraw participation in the trial at any time. Please see Consent Algorithm, Consent

Form

7. Randomisation and blinding

Four hundred opaque envelopes with sequential study numbers containing randomly

assigned treatment options (block randomisation; blocks of varying sizes of 8-12

envelopes) will be prepared and kept sealed in the Neurosurgical Theatres. When the

patient agrees to participate in the study, patient will undergo burr hole evacuation.

Pre-operatively, if it is judged safe the operating surgeon will request for an envelope

with the lowest number will be opened to determine the treatment option.

The nature of the surgical intervention does not allow for masking of the treatment

allocation. However, measures will be taken to minimise potential bias. Re-operation

will be indicated strictly on clinical grounds. The duration of hospital stay, mortality

data are not subject to bias. The follow up data will be filled in by subjects and their

family/carers by postal questionnaire.


Outcome measures

1. The primary endpoint is the recurrence rate.

The recurrence rate is defined as the rate of re-operation to treat recurrent CSDH in patients with CSDH previously treated with burr hole with or

without a drain. Recurrent CSDH is defined by the occurrence of symptoms and signs (see Clinical management below) attributable to an ipsilateral CSDH

demonstrated on a CT scan within six months of the original drainage procedure which is judged by the admitting consultant surgeon to be in need

of a further surgical procedure, including burr hole evacuation with or without drainage, percutaneous aspiration, craniotomy, or craniectomy.

2. The secondary endpoints are:

a. Mortality at 30 days and at six months b. Functional status at discharge - GCS, MRS, the presence of gross

neurological deficit (hemiparesis and dysphasia)

c. Functional status at discharge at six months-follow up – MRS,

mobility, type of accommodation required

d. The time to discharge from the neurosurgical unit

e. Presence of surgical and medical complications

8. Power The total number of patients will be 400 (200 in each arm of the study) for a 50%

difference in primary outcome (between 20% and 10% recurrence rates; power = 0.8;

p = 0.05). These figures are based on a literature review and retrospective audit of

CSDH patients undergoing surgery at Addenbrooke’s Hospital.

9. Clinical protocol

Patient will be treated in exactly the same way as per current practice, except that the

treatment option (whether to use the drain or not) will be decided through

randomisation and not by the surgeon (See Operation Protocol).

Patients age 18 or older presenting to the study centre with symptomatic, CT-proven

CSDH indicated for burr hole drainage will be screened against exclusion criteria and

suitable patients will be invited to take part in the trial. A formal consent will be

obtained (Consent Algorithm, Consent Form). If the patient is comatose or otherwise

unable to give informed consent, assent from the next of kin will be obtained prior to

surgery.

After obtaining a consent (or assent) the admitting neurosurgeon will fill in an

Admission Proforma detailing the subject’s baseline characteristics, including the presenting symptoms, presence or absence of a fall, baseline mobility, the level of


assistance they require in daily living, past medical history, Glasgow coma score

(GCS), modified Rankin scale (MRS), presence of limb weakness and dysphasia.

General anaesthesia or local anaesthesia will be indicated based on clinical condition

and patients’ preferences. In the operating theatre, the patient will be positioned

supine on a horseshoe headrest. Two 13 mm burr holes approximately 7 cm apart will

be drilled over the maximum width of the haematoma. The dura mater will be opened with a cruciate incision and the resulting cusps coagulated with bipolar diathermy.

The subdural collection will be washed out with warm Ringer’s lactate saline using a 50 ml syringe with or without a Jaques catheter. No special effort will be made to

disrupt subdural membrane loculations apart from those easily accessible via the burr holes. If at this stage it is judged safe to insert a subdural drain, randomisation will

take place. Bilateral CSDH will be treated as one case and both sides will receive the same treatment. If the patient is randomised to non-drain arm the subdural space will

be filled with Ringer’s lactate saline and the scalp closed in two layers. If the patient

is randomised to the drain arm a soft silicon drain (external diameter of 4.7 mm,

length of 90 cm; pfm Produkte für Medizin AG, Cologne, Germany) will be inserted

into the subdural space through the burr hole overlying the larger part of the subdural

cavity and tunnelled for minimum of 5 cm away from the scalp incision. The drain

will be connected to a soft collection bag that will be kept in a dependent position for

48 hours and then removed regardless of the amount drained. The operation note will

be recorded in a proforma (Operation Protocol).

At six months after surgery a follow up questionnaire with a stamped, self-addressed

envelope will be mailed to the study subjects (see Follow up Proforma). It consists of

two parts, the first part to be completed by the patient alone or with assistance, the

second part to be completed by a family member or a carer. In addition, alive/dead status will be determined for each patient using the NHS Strategic Tracing Service

and date of death will be obtained from hospital and general practice records.

10. Data management

Data collection, storage, analysis A set of proformas has been prepared to ensure standardised collection of data. They

are: Admission Form, Discharge Form, Operation Protocol form, Follow up Forms.

Each subject that entered the study will be assigned a study number. Each subject’s

baseline characteristics (as determined Admission Form) will be entered by a research

assistant into Database 1 (Excel database locked with a password). The database will be kept on a University of Cambridge computer. An independent research assistant

will collect outcome data into Database 2 (Excel database locked with a password). These databases will be inspected by the Data Monitoring Committee in regular

intervals (see below). Upon completion of the trial the databases will be merged for comprehensive data analysis.


The mortality data will be determined upon completion of the trial. The alive/dead

status will be determined for each patient using the hospital and general practice

records.

Radiological imaging will be collected prospectively and analysed upon completion

of the trial.

Baseline characteristics that will be used for comparison of the two treatment arms

will include: age, sex, past medical history (dementia, stroke, ischaemic heart disease, arrhythmia, COAD, DVT/PE, diabetes mellitus), drug history (antiplatelete,

anticoagulation), admission parameters (GCS, MRS, presence of gross neurological deficit (hepimaresis, dysphasia), haematoma characteristics (side, CT findings –

density, per-operative findings – subdural fluid pressure and appearance, the presence and appearance of subdural membranes, brain expansion).

The primary outcome (recurrence rate) analysis will be performed on intention to treat

basis using an appropriate frequency comparison test (χ2 or Fisher’s tests). Secondary

outcome measures will be analysed using the appropriate test depending on the type

of data. Categorical frequencies will be compared using χ2 or Fisher’s exact test.

Numerical data will be tested for normality using the Kolmogorov-Smirnov test and if

normally distributed the t-test will be used. Alternatively the Mann-Whitney U test

will be used. The baseline characteristics of non-responders to the follow up

questionnaire will be compared with those of responders. In addition, baseline

characteristics of non-responders in the “drain” group will be compared with those of

non-responders in the “non-drain” group using appropriate statistical tests (χ2 or

Fisher’s exact tests for comparison of proportions and t-test or Mann-Whitney U for

comparison of means).

Linear regression model analyses will be performed for primary and secondary outcomes. The recurrence rate, mortality, the duration of neurosurgical hospital stay

and MRS will be used as dependent variables.

Data Monitoring Committee The recurrence rate and complications in the two experimental arms will be compared

after every fifty new participants are entered. Discontinuation of the trial will be

recommended if:

1. There is a significantly higher frequency of adverse effects in one arm of the

study.

2. There is a significant reduction in the recurrence rate in either arm of the

study.


11. Ethical approval The study has been approved by the Cambridgeshire 2 Research Ethics Committee on

23 September 2004 (REC No 04/Q0108/52.

12. Indemnity arrangements

Indemnity arrangements are in place in the Academic Department of Neurosurgery

conforming to the requirements of the University of Cambridge and the

Addenbrooke’s Hospital NHS Trust.

13. Publication

The results of the Trial will be published in peer-reviewed journals and meetings.

14. References

(1) McKissock W, Richardson A, Bloom W. Subdural haematoma. A review of 389 cases. Lancet,

1365-1369. 25-6-1960.

(2) Kudo H, Kuwamura K, Izawa I, Sawa H, Tamaki N. Chronic subdural hematoma in elderly

people: present status on Awaji Island and epidemiological prospect. Neurologia Medico-

Chirurgica 1992 April;32(4):207-9.

(3) Kinsella K, Velkoff VA. An Aging World: 2001. U.S.Census Bureau Series P95/01-1, 9. 2001.

Washington, DC, U.S. Government Printing Office.

(4) Haines DE, Harkey HL, al Mefty O. The "subdural" space: a new look at an outdated concept. Neurosurgery 1993 January;32(1):111-20.

(5) Weigel R, Schmiedek P, Krauss JK. Outcome of contemporary surgery for chronic subdural

haematoma: evidence based review.[comment]. Journal of Neurology, Neurosurgery &

Psychiatry 2003 July;74(7):937-43.

(6) Lind CR, Lind CJ, Mee EW. Reduction in the number of repeated operations for the treatment of

subacute and chronic subdural hematomas by placement of subdural drains. Journal of

Neurosurgery 2003 July;99(1):44-6.

(7) Santarius T, Hutchinson PJ. Chronic subdural haematoma: time to rationalize treatment? Br J

Neurosurg 2004 August;18(4):328-32.

(8) Laumer R, Schramm J, Leykauf K. Implantation of a reservoir for recurrent subdural hematoma

drainage. Neurosurgery 1989 December;25(6):991-6.


(9) Tsutsumi K, Maeda K, Iijima A, Usui M, Okada Y, Kirino T. The relationship of preoperative

magnetic resonance imaging findings and closed system drainage in the recurrence of chronic

subdural hematoma. Journal of Neurosurgery 1997 December;87(6):870-5.

(10) Wakai S, Hashimoto K, Watanabe N, Inoh S, Ochiai C, Nagai M. Efficacy of closed-system

drainage in treating chronic subdural hematoma: a prospective comparative study. Neurosurgery

1990 May;26(5):771-3.

(11) Dunn LT. Surgery for chronic subdural haematoma: is there an evidence base? J Neurol

Neurosurg Psychiatry 2003 July;74(7):842.


15. Appendices









Documents

CSDH-Trial RESEARCH PROTOCOL v-23-5-05 1€¦ · demonstrated on a CT scan within six months of the original drainage procedure which is judged by the admitting consultant surgeon