Traumatic Brain Injury Associated Radiological DVT Incidence and Significance Study
Traumatic Brain Injury Associated Radiological DVT Incidence and Significance Study
Whilst deep vein thrombosis (DVT) is common following traumatic brain injury (TBI), optimal
 timing and safety of pharmacological prophylaxis is uncertain. Paradoxically the harm
 associated with the occurrence of is also unclear.

 This study is an observational pilot that aims to define the incidence of proximal DVT in
 patients with moderate to severe TBI. It seeks prospectively to determine if there is an
 association between DVT and outcome. It also seeks to explore possible associations between
 the occurrence of DVT and the incidence of lung injury and/or ventilator associated
 pneumonia.
Deep Venous Thrombosis (DVT) is common following trauma and patients with TBI are at
 increased risk. In studies of TBI that screened for DVT in the proximal lower limb veins, the
 incidence is between 14 and 18%. Pharmacological thromboprophylaxis (PT) may be effective in
 reducing the incidence of DVT following TBI. However, there is a reluctance to commence it
 due to concerns about the risk of intracranial haematoma expansion and contusion enlargement.
 PT is therefore often delayed, exposing patients to potential risks and complications of DVT.
 Recent systematic reviews could not answer the question of when to commence PT as no high
 quality randomised controlled trials addressing this question have been conducted. The latest
 edition of the Brain Trauma Foundation Guidelines could not make a recommendation on this
 issue . A Delphi exercise involving the investigator's network of United Kingdom(UK)
 Eurotherm3235 study centres found that the leading concern of specialists in UK neurocritical
 care, that they felt required further study, was when to commence PT following moderate to
 severe TBI.

 Paradoxically however, despite these concerns over the use of PT in this population of
 patients, evidence of harm associated with the confirmed presence of proximal DVT is not yet
 convincing. This has additional significance as without clear evidence of harm associated
 with DVT complicating TBI, trials to address the questions of safety and efficacy of earlier
 use of PT are difficult to design and unlikely to attract the necessary funding.

 From a search of a trauma registry of patients at risk of DVT who underwent venous screening,
 in TBI patients the occurrence of DVT was associated with increased ventilator days (Mean
 (SD), 18.0 (14.9) vs. 9.3 (7.9) days for DVT vs. no DVT, p=0.014) and ICU length of stay
 (23.0 (14.5) vs. 13.1 (9.8) days for DVT vs. no DVT, p=0.006). Similar results were seen in a
 post hoc analysis of the EPO TBI trial. This was a randomised controlled trial (RCT) of the
 effect of erythropoietin (EPO) verses placebo on outcome following TBI. Repeated lower limb
 screening for the presence of DVT was conducted as part of the protocol. Both ventilator days
 (Median (IQR) 11 (6-17) vs. 8 (4-14) days for DVT vs. no DVT, p<0.001) and ICU length of stay
 (17 (11-22) vs. 12 (6-19) days DVT vs. no DVT, p<0.001). Good neurological outcome at 6
 months was significantly less frequent in those that developed DVT (45.4 vs. 57.9% DVT vs. no
 DVT, p=0.01). Whilst these findings are clinically important they are the result of
 retrospective and post hoc analysis. They therefore require to be prospectively validated if
 they are to be accepted.

 One possible explanation for an increase in ventilator dependency and ICU length of stay
 could be the occurrence of undiagnosed pulmonary emboli causing acute lung injury (ALI). The
 occurrence of ventilation perfusion mismatching, deterioration in arterial partial pressure:
 fraction inspired oxygen ratio (PaO2:FiO2) and radiological changes on chest x-ray, being
 interpreted as evidence of pulmonary infection. This is supported by local audit data from
 June to October 2017 which found that 37% of brain injured patients had a clinical diagnosis
 of ventilator associated pneumonia (VAP) and were treated with antibiotics but lacked
 subsequent microbiological confirmation. It is also possible that small pulmonary emboli
 might predispose to pulmonary infection, explaining why the incidence of ventilator
 associated pneumonia (VAP) remains high in this population (40%, in the same local audit)
 despite the adoption of measures which have lowered VAP rates in other critically ill patient
 groups.

 Lung Brain "cross-talk" could link evidence of ALI to a negative impact on neurological
 outcome in these patients. A disproportionate increase in mortality in patients with TBI and
 ALI has been reported. This was greatly in excess of deaths attributable to pulmonary
 dysfunction. Similarly, in animal models, ALI was found to be associated with cognitive
 impairment, and biomarker/histological evidence of neuronal injury.

 This is a prospective, potentially multi centre, observational pilot study that aims to
 determine the incidence of DVT after TBI. Patients admitted to an ICU within 72 hours of
 suffering a TBI will be eligible for inclusion. The study will run for 2 years with a 16
 month recruitment period. Based on current activity in Edinburgh the investigators estimate
 that 50 to 60 patients will be eligible for recruitment over the course of the study. In
 order to ensure satisfactory recruitment, the investigators will also approach centres that
 have expressed an interest.

 Once consent is obtained for the patient to be enrolled in the study, a compression
 ultrasound scan (USS) of both legs will be carried out as soon as possible so that the first
 USS is completed within 72 hours of injury. USS will be repeated on alternate days up to Day
 10 from injury. Daily data collection will include information on the use of mechanical and
 pharmacological thromboprophylaxis, ventilator dynamics including FiO2 and PaO2, chest X ray
 reports, clinical and microbiological diagnosis of ventilator associated pneumonia,
 ventilator days and ICU and hospital length of stay. The Modified Oxford Handicap Scale will
 be completed for all patients on day 28, hospital discharge or death whichever is sooner
 Patients will then be followed up at 6 months by the study team, at which time an extended
 Glasgow Outcome Scale Questionnaire will be completed.

 An amendment to the protocol is also being prepared to include assessment of blood
 coagulation by standard laboratory testing and viscoelastic methods.
Inclusion Criteria:

 1. Age ≥ 16 years

 2. Admission to critical care

 3. moderate/severe, non-penetrating traumatic brain injury

 4. Abnormal brain CT Scan

 5. Post resuscitation Glasgow coma score (GCS) ≤12, or GCS motor component ≤5

 6. Able to complete consent and first USS within 72 hours of injury

 Exclusion Criteria:

 1. Normal brain CT scan

 2. Unlikely to survive for the next 24 hours in the opinion of the ICU Consultant or
 Consultant Neurosurgeon treating the patient

 3. Contra indication to normal prophylactic measures, including heparin, were indicated

 4. Known blood clotting disorder or thrombophilia

 5. Significant pelvic or lower limb trauma

 6. Malignancy

 7. Pregnancy or recently post-partum