ORIGINAL ARTICLE

Title:

A National Survey of Thromboprophylaxis in Traumatic Brain Injury in the United Kingdom

Running title:

TBI Thromboprophylaxis Survey

Authors:

Aimun Jamjoom1, Aswin Chari2, Julita Salijevska2, Roseanne Meacher2, Paul Brennan1, Patrick Statham1

Institution:

1 Department of Clinical Neuroscience, Western General Hospital, Edinburgh

2Intensive Care Unit, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London

Word count: 2808 words

Abstract

Introduction

Patients with traumatic brain injury (TBI) are at increased risk of venous thromboembolic events

(VTE). In this survey we aimed to assess current practice in the United Kingdom and identify areas of

variation for further investigation.

Methods

We distributed a case-based survey to neurosurgical consultants and trainees via e-mail. The survey

included four index TBI cases commonly seen: a surgically treated acute extradural haematoma,

bilateral frontal contusions treated conservatively, diffuse axonal injury requiring critical care and a

conservatively managed small acute subdural haematoma. Each case vignette included questions

looking at a range of areas regarding thromboprophylaxis.

Results

Sixty-two responses were collected among UK neurosurgeons with a good geographic distribution. In

each case, over 90% of respondents would initiate mechanical prophylaxis (MTP) at admission. There

was greater variation on the decision to commence pharmacological prophylaxis (PTP). Consultants

showed a higher willing to commence PTP across all cases (84%) compared to trainees (77.4%). Low

molecular weight heparin (LMWH) was the favoured PTP agent in over 90% of respondents. There

was significant variability in the timing of initiation of PTP within and between cases. The median

times to commence PTP across all four cases ranged from 1-7 days.

Conclusion

This survey highlighted broad consensus on the use of MTP and choice of PTP agent, when used.

However, the survey also demonstrated wide intra-case variation on whether to start PTP and

particularly the timing of initiation. This discordance in practice shines light on the lack of evidence

guiding thromboprophyalxis in TBI and adds weight to the need for prospective randomized trials to

guide clinical management.

Keywords

Traumatic Brain Injury – thromboprophylaxis – national survey

Introduction

Patients with traumatic brain injury (TBI) are at increased risk of venous thromboembolic events (VTE)

due to a number of factors including immobility and the systemic response to trauma and surgery 1.

Approaches to reduce the risk of VTEs include mechanical thromboprophylaxis (MTP) which

compromises graduated compression stockings (GCS) and intermittent pneumatic compression (IPC).

The evidence underlying the use of MTP is mixed and has primarily been extrapolated from the

general trauma, intensive care and neurosurgical population. Turpie found that GCS alone or in

combination with IPC reduced the incidence of VTE compared to control in a population of

neurosurgical patients which included TBI2. Conversely, Arabi found IPC superior to GCS in population

of patients in intensive care3. This finding mirrored a large randomized prospective trial in the stroke

population that found a significant reduction in VTE incidence in the IPC group compared to control

and indicated that the intervention may possibly also improve survival4.

The evidence underlying the use of pharmacological thromboprophylaxis (PTP) is similarly mixed and

is further complicated by the challenge of balancing the risk of worsening intracranial bleeding with

VTE propagation. A survey in 2001 found that only 58% of neurosurgical units used PTP in the TBI

population with a wide variation in the preferred starting time5. Despite this finding over a decade

ago, there is still little data to guide clinicians on the optimal timing and methods of PTP in TBI. A

meta-analysis looking at the optimal timing to commence PTP found no level I evidence to guide

timing but demonstrated a reduced risk of VTE in TBI patients who had PTP commenced within 72

hours from injury without an increase in intracranial injury progression6. The 2007 guidelines of the

Brain Trauma Foundation suggest that there was Level III evidence to support the use of MTP until the

patient is mobile7. It also suggests that there is Level III evidence for the use of PTP but warns of “an

increased risk for expansion of intracranial haemorrhage”. Similarly vague recommendations were

made in a major review of thromboprophylaxis by Geerts and colleagues8. For trauma patients, their

recommendation was to combine optimal mechanical prophylaxis with Low Molecular Weight

Herparin (LMWH) as soon as it is considered safe to do so. These recommendations were for general

trauma patients which included TBI cases but the review did not provide focused advice on differing

TBI subtypes.

Whilst awaiting more robust data to guide decision-making, clinicians must use their judgment on an

individual patient basis to decide upon the timing and mode of thromboprophylaxis in these patients.

In addition to the risks of worsening intracranial bleeding, a number of other factors must also be

considered, such as other injuries, timing of surgical intervention and predisposing risk factors for and

against venous thromboembolic disease. The present study aims to assess current

thromboprophylaxis practice amongst neurosurgeons working in the United Kingdom. We chose a

case-based approach given the wide variation in TBI cases in an attempt to highlight areas of

uniformity and disparity and acting as foundation for future research.

Methods

A case-based survey consisting of four cases was designed to cover the major sub-types of TBI with a

range of VTE risk factors and important management considerations. The four vignettes topics were

as followed:

i) Acute extradural haematoma treated with a craniotomy

ii) Bilateral frontal contusions treated conservatively in a patient on Warfarin

iii) Diffuse axonal injury requiring critical care and monitoring with an ICP bolt

iv) Conservatively managed small acute subdural haematoma

The cases all follow a similar format to aid ease of completion. Each case asked about the choice and

timing of initiation of MTP and PTP, the use of IVC filters and the main factors guiding clinician’s

decision making process. The full questionnaire is supplied online (Appendix 1) and the full case

vignettes are shown in Table 1. Following a pilot at a single neurosurgical centre, it was peer-reviewed

by the Society of British Neurological Surgeons (SBNS) Academic Committee and distributed

electronically to consultant and trainee-level members of the Society of British Neurological Surgeons

(SBNS) and British Neurosurgical Trainee Association (BNTA) via e-mail lists. Recipients on these

mailing lists included consultants and specialty trainee across the UK. The questionnaire was sent out

via both mailing lists on three separate occasions to maximize the response rate. The number of

recipients was calculated by contacting the SBNS and the Surgical Special Advisory Committee (SAC)

for the size of the consultant and trainee population in the UK. This was determined to be 589 (349

consultants and 240 specialist trainees). Responses were collated electronically and analyzed in

Microsoft Excel (© Microsoft Inc).

Results

A total of 62 responses were received, with 24 (39%) from consultants and 38 (61%) from specialist

trainees. The overall response rate was 10.5% with a consultant response rate of 7% and trainee rate

of 16%. There was a good geographical distribution of responses covering 79% of regions within the

UK. Figure 1 demonstrates a weighted geographical response rate.

Case 1: Extradural haematoma (EDH) managed surgically

Fifty-eight (93.5%) respondents would initiate MTP at admission, with 12 (20.7%) preferring IPC, 13

(22.4%) GCS and 33 (56.9%) using both. Fifty-eight (93.5%) would also initiate PTP, 55 (94.8%) of

which would use LMWH. Time of initiation ranged from <24h to 7 days with a median time epoch of

1-3 days (Figure 2). Only 19 respondents (32.8%) would repeat a CT scan prior to starting PTP and only

1 (1.6%) would use an IVC filter in this patient. The major factor dictating decision-making in this case

was the type of injury followed by the surgical management (Figure 3).

Case 2: Cerebral contusions in patient on Warfarin

A large majority (96.7%) of respondents would initiate MTP on admission. There was variation in the

mode of MTP: 40.7% preferred GCS only, 5% went for IPC alone and just over half (50.8%) would use

both modes together. Only 46 respondents (75.4%) would commence PTP with the majority (91.3%)

using LMWH. Timings of PTP initiation varied widely between < 24 hours to > 7 days post-injury as

shown in Figure 2. The median time to initiation was 3-7 days post-injury. Three (5.1%) would use an

IVC filter and the primary clinical factor guiding decisions was the type of intracranial injury (Figure 3).

Case 3: Diffuse axonal injury (DAI) with extended critical care management

Fifty-seven (96.6%) respondents would initiate MTP at admission: 13 would have used IPC (22.8%), 9

(15.8%) GCS and 35 (61.4%) would have used both. All respondents would start PTP in this case with

the majority (94.8%) using LMWH. Timing to commence PTP ranged across all time epochs but the

majority of respondents (65.5%) would have started PTP within the first 3 days of admission (Figure

2). Twelve respondents (21.1%) would use an IVC filter. In this case, the history of a previous DVT

featured as an important clinical factor guiding clinician decision-making (Figure 3).

Case 4: Conservatively managed acute subdural haematoma (SDH)

Fifty-four (93.1%) would initiate MTP at admission with 32 (59.3%) using GCS, 2 (3.7%) using IPC and

20 (37.0%) using both. Only 28 (49.1%) would start PTP of which 26 (92.9%) would have used LMWH.

Timings were highly variable from <24h to >7 days with a median time epoch of 1-3 days post-injury.

No respondents would use an IVC filter and the main guiding factor was the mobility of the patient

(Figure 3).

Comparison between consultants and trainees

We assessed differences between consultant and trainee practice across all four cases with regard to

their decision on commencing MTP and PTP. Trainees were more robust in their approach to

commencing MTP with a higher average percentage of trainees (98%) commencing MTP for all cases

compared to the consultant cohort (90%). The difference was most pronounced in the case 4

(conservatively managed acute SDH) where 100% of trainees would have commenced MTP compared

to only 83.3% of consultants. The reverse was true regarding PTP: consultants showed a higher willing

to commence PTP in all cases (84%) compared to trainees (77.4%). The starkest difference between

the two cohorts was in case 4 where 56% of consultants would have commenced PTP compared to

only 44% of trainees. There was no difference in the median time of commencing PTP between

trainees and consultants across all four cases.

Discussion

This national neurosurgical survey has identified areas of concordance and discordance in the practice

of thromboprophylaxis in TBI. There was broad agreement (>90% in each case) on the initiation of

MTP on admission, however there was debate over the choice between GCS and IPC devices. In three

cases (surgically managed EDH, DAI in critical care and cerebral contusion on warfarin), the majority

of respondents opted for both GCS and IPC. In case 4 (conservatively managed SDH), the majority

opted for GCS only. This is likely driven by the fact that case 4 stated that the patient had been mobile

throughout their admission. The evidence underlying the use of MTP is mixed and there is currently

no level 1 evidence to direct their use in the TBI population. A trial by Turpie found no difference in

VTE rates between GCS and IPC in the general neurosurgical population 2. However, a meta-analysis by

Collens looking at 30 studies assessing thromboprophylaxis in neurosurgical patients (that included

TBI patients) found that compared to placebo, IPC [1.9 (0.6-3.3)] had a lower rate of VTE compared to

GCS [11.6 (3.4-19.8)]9.

There was a more heterogeneous response to the question of whether or not to initiate PTP - ranging

from 100% (case 3: DAI in critical care) to 49.1% (case 4: conservatively managed SDH). The variation

in case 4 was likely driven by the patient’s mobility which for a significant portion of respondents

negated the need to commence PTP. Across all cases, we found concordance regarding the choice of

agent with >90% of respondents in each case using LMWH. A number of studies have assessed the

differences between LMWH and unfractionated heparin with mixed results. Arnold and colleagues

failed to find significant differences between LMWH and unfractionated heparin in a general trauma

population10. Conversely, Minshall et al retrospectively looked at differences in VTE rates and ICH

progression between patients treated with either LMWH or unfractionated heparin 11. The study found

lower rates of VTE and ICH progression in the LMWH cohort though their injury scores were lower

compared to the unfractionated heparin group. Collen’s meta-analysis of studies assessing

thromboprophylaxis in neurosurgical patients found no significant difference in a head-to-head

comparison between LMWH and unfractionated heparin’s efficacy and safety9. However, a larger

meta-analysis looking at all randomized controlled trials that compared LMWH and UFH found that

they had similar effectiveness against VTE but UFH had a higher haemorrhage complication rate12.

This likely explains why practice in the UK has congregated towards the use of LMWH despite the

absence of class I evidence in the TBI population.

The decision to commence PTP is complicated by the question of optimum timing to do so. This

difficulty in decision-making was reflected in the wide intra-case variation in practice demonstrated by

our survey. Cupitt found similar divergence in practice on the timing of PTP in TBI patients in a survey

of neurosurgical units in the UK in 20015. A meta-analysis of five retrospective studies totaling 1624

patients found that early (<72h) initiating of PTP had both a lower risk of VTEs [hazard ratio 0.52 (CI

0.37-0.73)] and ICH progression [hazard ratio 0.64 (CI 0.35, 1.14)]6. However, these findings were

significantly biased due to the retrospective nature of the included studies. A pilot RCT (DEEP I)

looking at low risk TBI (small, stable and conservatively intracranial haematomas) found subclinical

radiographic ICH progression in 5.9% in the early PTP cohort (24 hours) compared to 2.3% in the late

cohort (96 hours)13. There was a single DVT in the placebo group and no deaths or clinically significant

ICH progressions in either cohort. This trial was a pilot and was not powered to find significant

differences between the two cohorts. There is currently a prospective randomized trial recruiting

which is looking at the timing of PTP in TBI. It is comparing early (36-48h) vs late (>96h) initiation of

PTP in the context of traumatic ICH (OPTTICH trial) (Clinicaltrials.gov, accessed 12/08/2015). The data

from this trial should help begin to answer this key question; however its primary outcome measure is

proximal lower limb DVT diagnosis from bi-weekly screening rather than clinically significant

thromboses or mortality and morbidity – in fact, the trial does not include either in their outcome

measures. The issue of outcome in thromboprophylaxis trials remains a contentious one. DVT

screening will increase the pick-up rate and therefore lower sample size requirements, however the

clinical significance of asymptomatic, radiologically diagnosed DVTs is not established. A similar

argument is applicable to the safety arm of these trials as it is not known whether radiologically

worsening intracranial bleeding observed on ‘scheduled’ CT scans correlates with worse clinical

outcomes. A more relevant approach would be to assess patient mortality and morbidity as the

primary outcome. By using Jamjoom et al’s review6 we identified two studies that included patient

mortality within their analysis when comparing early (<72 hours) versus late (>72 hours) PTP14 15. The

mortality of patients in the early PTP cohort was 4.4% and in the late group was 6.2%. By using these

values, an approximate sample size calculation with α=0.05 and β=80% required a total study

population of 4862. This large project study population highlights the difficulty with using mortality as

the primary outcome. However, it should be noted that this value were derived from retrospective

cohort studies which may skew the approximations. A better approach would be the use of a

functional outcome score such as the extended Glasgow Coma Score (GOSE) which may provide a

more manageable study population. There is little data on patient functional outcome based on PTP

timing in the literature. We would therefore advocate establishing a trial assessing early (48-72h)

compared to late (>96h) PTP that had the GOSE as its primary outcome measure. The trial would aim

to have broader inclusion criteria compared to other trials including all TBI patients regardless of

whether they were managed surgically or not.

The issue surrounding IVC filters is perhaps even more contentious, with between 0-21.1% of

respondents saying they would use them in each of the four cases. A recent survey of intensive care

units in the UK suggests that only 36% of major trauma centres use IVC filters prophylactically, with

the most common indication for insertion being severe brain injury that precludes PTP in the context

of pelvic/lower limb injury16. There is currently little evidence to guide the use of IVC filters and

therefore the latest edition of the American College of Chest Physicians guidelines do not support

their use in major trauma17.

Our survey used a case-based approach in an attempt to glean a more nuanced insight into

respondents’ approach to a range of clinical TBI situations. We believe this approach was more robust

and provides more meaningful data than broad questions as in the only previous survey done on this

subject5. However, the survey is limited by its small response rate and the fact the majority of

respondents are trainees. This curtails the generalizability of the results however the spread of

geographical responses indicates that the study provides a broadly representative sample of national

practice. The evidence of significant variation in practice in our studied cohort, particularly on

whether and when to commence PTP, highlights the weak evidence-base. This satisfies the aims of

the study and provides a foundation and direction for future research.

Conclusion

In conclusion, our national neurosurgical survey has helped quantify areas of concordance and

discordance in the practice of the UK neurosurgical community regarding the use of

thromboprophylaxis in TBI. Whilst the majority of respondents are in broad agreement about the

initiation of MTP, there is limited agreement on the use, and particularly the timing, of PTP in the TBI

population. There is a slowly growing body of evidence to help guide practice with a number of

prospective trials underway focusing on the timing of PTP which will help address the variation in

practice observed in our survey. However, these trials will be limited by endpoints that have

questionable clinical relevance. Furthermore, despite the Brain Trauma foundation highlighting the

lack of level I evidence, there are currently no planned trials focusing on the efficacy of MTP in the TBI

population. Following the clear demonstration of efficacy of IPC in the stroke population, there is a

need for a large pragmatic RCT of this intervention in the TBI population. Given the highly

heterogeneous nature of the TBI population, we believe the future of thrombroprophylaxis in TBI will

centre around the use of stratification pathways that stream patients into differing

thromboprophylaxis protocols based upon the type and severity of their intracranial injury and other

associated VTE risk factors.

Declaration of interest

The authors report no declaration of interest

Acknowledgments

We would like to extend our warm thanks to all the respondents who took the time to complete the

questionnaire.

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Figures

Figure 1: Weighted geographical distribution of respondents, according to healthcare region.

Figure 2: Distributions of timings of initiation of pharmacological thromboprophylaxis in each of the 4

cases. There is considerable variation in the timings of initiation and their distributions across the

cases.

Figure 3: Reasons given by respondents the main factor driving decision making in each case.

Generally, injury type and assessment of the patient’s mobility seem to be important factors but

some consideration was given to other factors too.