There are insufficient data to support a Level I recommendation for this topic.

There are insufficient data to support a Level II recommendation for this topic.

Graduated compression stockings or intermittent pneumatic compression (IPC) stockings are recommended, unless lower extremity injuries prevent their use. Use should be continued until patients are ambulatory.

Low molecular weight heparin (LMWH) or low dose unfractionated heparin should be used in combination with mechanical prophylaxis. However, there is an increased risk for expansion of intracranial hemorrhage.

There is insufficient evidence to support recommendations regarding the preferred agent, dose, or timing of pharmacologic prophylaxis for deep vein thrombosis (DVT).

Patients with severe TBI are at significant risk of developing venous thromboembolic events (VTEs) with their accompanying morbidity and mortality. In a review of data from the National Trauma Databank, Knudson et al. found TBI (AIS ≥ 3) to be a high risk factor for VTE (odds ratio 2.59). The risk of developing deep venous thrombosis (DVT) in the absence of prophylaxis was estimated to be 20% after severe TBI.

Rates of DVT vary depending on the methods used for detection. Clear distinctions need to be made between clinically evident DVTs and those detected by laboratory investigations (Duplex scanning, venography, radiolabeled fibrinogen scans) in asymptomatic patients. Most DVTs diagnosed by screening tests are confined to the calf, are clinically silent, and remain so without adverse consequences. However thrombi involving the proximal leg veins are more likely to produce symptoms and result in a pulmonary embolus (PE). A review of the Pennsylvania Trauma Outcomes Study by Page et al, found an incidence of PE of 0.38% in TBI patients during their acute hospital stay.

PE is known to be associated with high rates of morbidity and mortality in hospitalized patients. Treatment of PE in neurosurgical patients is often complicated by uncertainty regarding the safety of anticoagulation among patients who have recently undergone craniotomy or suffered intracranial hemorrhage from trauma. Furthermore, a high proportion of patients who develop DVTs have residual venous abnormalities: persistent occlusion and/or venous incompetence, leg swelling, discomfort, or ulcers that diminish quality of life. All these manifestations of VTEs, make prevention critical.

Options for prevention of VTE in neurosurgical patients include both mechanical (graduated compression stockings, intermittent pneumatic compression stockings), and pharmacological (low-dose heparin, and low-molecularweight heparin) therapies. Intuitively, mechanical therapies carry less associated risk. A study by Davidson et al. did not find any change in mean arterial pressure, intracranial pressure, or central venous pressure in TBI patients receiving ICP monitoring with the initiation of sequential pneumatic compression devices.4 However, lower extremity injuries may prevent or limit their use in some trauma patients and the devices may limit physical therapy and progressive ambulation. Risks associated with the use of LMWH and low-dose heparin include both intracranial and systemic bleeding, the effects of which may range from minor morbidity to death. Any decision regarding the use of these anti-VTE therapies must weigh efficacy against harm from the proposed intervention.

For this new topic, Medline was searched from 1966 through April of 2006 (see Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 37 potentially relevant studies, 5 were included as evidence for this topic (Evidence Table I).

In 1986, Black et al. published a prospective cohort study of 523 patients, of whom 89 had TBI, all treated with intermittent pneumatic compression stockings. Rates of clinically apparent DVT and PE were determined. The incidence of VTE in the entire study group with intracranial disorders was 3.8%, with no cases of VTE detected in patients with TBI.

A number of studies have assessed the efficacy of mechanical interventions in preventing DVT in neurosurgical patients. The first such report by Skillman et al. in 1978 enrolled 95 patients randomized to treatment with intermittent pneumatic compression stockings and no treatment. Patients were screened for DVT with daily radiolabeled fibrinogen scans, and those with positive scans underwent venography to confirm the diagnosis. The authors found an 8.5% incidence of DVT in the treatment group compared with a rate of 25% in untreated controls (p < 0.05). However, no data regarding patients specifically with TBI were presented. In 1989, Turpie et al. reported the results of a randomized study in 239 neurosurgical patients of whom 57 had TBI. Radiolabeled fibrinogen scanning or impedence plethysmography was used to screen for DVT, with venography performed if either test was abnormal. Patients were randomized to graduated compression stockings, graduated compression stockings plus IPC, or no treatment, with DVT rates of 8.8%, 9%, and 16%, respectively. Ten deaths were reported in the group treated with compression stockings alone, none thought to be due to VTE. One case of PE was found on post-mortem examination in this group, but cause of death was attributed to massive cerebral edema. In each of the two other groups, four deaths were reported, none attributed to VTE.

The demonstrated efficacy of mechanical measures to prevent DVT in neurosurgical, multisystem trauma, and TBI patients, along with the minimal side effects, lead us to recommend their use in all patients with severe TBI. However, because of the lack of Class II data specific to TBI on this topic, the recommendation must be made at Level III. Obviously, the use of graduated compression and IPC stockings may be limited by lower extremity injuries.

In 2002, Kim et al. reported a case series of 64 patients admitted to a Level I trauma center with severe TBI. DVT prophylaxis consisted of 5000 units of subcutaneous heparin given twice daily. For analysis patients were grouped according to time of prophylaxis initiation: less than or greater than 72 h following admission. No differences in rates of DVT, PE, or death were found between groups. However, the small sample size and retrospective nature of the study preclude any conclusions regarding efficacy or safety of early versus late prophylaxis with low-dose heparin after TBI. Also in 2002, Norwood et al. conducted a prospective study of 150 patients with TBI treated with enoxaparin 30 mg twice daily beginning 24 h after arrival to the emergency department. The rate of clinically evident DVT was 4%. Notably, during this study the protocol for initiation of enoxaparin therapy was changed to 24 h following any neurosurgical intervention, after two of 22 patients (9.1%) who underwent craniotomy, developed post-operative bleeding while receiving surgical evacuation. The rate of bleeding complications in patients treated non-operatively was 3%. The rate of Doppler-detected DVT reported by Norwood was lower compared to historical controls; however, there was a higher incidence of bleeding complications with early initiation of enoxaparin therapy.

In 2003, Kleindienst et al. reported a case series of 940 neurosurgical patients, including 344 patients with TBI who were treated with compression stockings and certoparin 18 mg once daily within 24 h of admission or surgery. Prophylaxis with certoparin was initiated in TBI patients only when a head CT within 24 h of admission or surgery did not show any progression of intracranial bleeding. Patients did not receive certoparin if they were chronically treated with oral anti-coagulant or antiplatelet therapy, or had abnormal coagulation studies, platelet aggregation test, or platelet count below 100,000/mL on admission. Among patients in whom DVT was suspected on clinical grounds, the diagnosis was confirmed with Duplex sonography or venography. Among the 280 TBI patients who received certoparin, none were diagnosed with VTE. However, nine study patients (3.2%) with TBI had progressive intracranial hematoma, eight of whom received re-operation. Four of the nine TBI patients with an expanding intracranial hematoma received certoparin prior to the screening CT scan. Nevertheless, the observed rate of patients with expanding intracranial hematoma receiving reoperation in this retrospective series again raises concern for harm.

In 2003, Gerlach et al. reported a prospective cohort study of 2,823 patients undergoing intracranial surgeries who were treated with nadroparin (0.3 mL/day) and compression stockings within 24 h of surgery. This study included 231 patients with TBI (81 subdural hematomas, 47 epidural hematomas, 42 cranial fractures, and 61 decompressive craniectomies). No clinically apparent VTE was reported among patients with these lesions. However, DVT was identified in one patient undergoing surgical reconstruction of the basal frontal cranial region after severe TBI and in another after evacuation of a chronic subdural hematoma. The rate of clinically significant post-operative hematomas in patients undergoing evacuation of acute subdural hematomas was 2.5%, 0% in patients with epidural hematomas, and 1.6% following decompressive craniectomy. This study raises the possibility that different TBI pathologies have different risks from prophylaxis with LMWH. However, subset analysis is limited by both small sample size and lack of a control group.

Though studies regarding pharmacologic DVT prophylaxis in patients with severe TBI along with studies from elective neurosurgical patients suggest that low-dose heparin or LMWH is efficacious in reducing the risk of VTE, the available data show a trend toward increased risk of intracranial bleeding. Case studies suggest that pharmacologic prophylaxis should not be initiated peri-operatively, but when it is safe to begin such therapy in patients with severe TBI remains poorly defined. Moreover, no recommendations regarding drug choice or optimal dosing in neurosurgical patients can be made based on current evidence.

Several studies have compared the efficacy and complication rates of LMWH or low-dose heparin in preventing DVT in patients undergoing elective neurosurgical procedures against treatment with mechanical prophylaxis. Agnelli et al. compared enoxaparin (40 mg once daily) begun 24 h post-operatively with compression stockings alone in patients undergoing elective cranial or spinal surgery. Lower rates of DVT were found in patients receiving enoxaparin in comparison to those treated with graduated compression stockings alone (17% vs. 32%, p = 0.004). Lower rates of proximal DVT (5% vs. 13%, p = 0.04) were also seen. No significantly increased risk of major (3% vs. 3%) or minor (9% vs. 5%) bleeding complications was noted between groups. Similarly, Nurmohamed et al. found non-significant lower rates of proximal DVT or pulmonary embolism (6.9% vs. 11.5%, p = 0.065) in patients treated with nadroparin and graduated compression stockings, compared to those treated with graduated compression stockings alone. However, a trend towards a higher rate of major bleeding complications (2.5% vs. 0.8%, p = 0.087) was found in nadroparin-treated patients. These studies suggest that DVT prophylaxis with pharmacological agents is more efficacious than mechanical measures alone in preventing DVT in neurosurgical patients. However, any attempt to extrapolate data from elective neurosurgical patients to patients with TBI must be viewed with caution, as the later frequently have intracranial hemorrhages at risk of expansion.

Level III evidence supports the use of graduated compression or IPC stockings placed for DVT prophylaxis for patients with severe TBI, unless lower extremity injuries prevent their use. Level III evidence supports the use of prophylaxis with low-dose heparin or LMWH for prevention of DVT in patients with severe TBI. However, no reliable data can support a recommendation regarding when it is safe to begin pharmacological prophylaxis. Moreover, no recommendations can be made regarding medication choice or optimal dosing regimen for patients with severe TBI, based on the current evidence.

A randomized controlled trial (RCT) of mechanical prophylaxis alone versus with the addition of pharmacological prophylaxis of DVT in patients with severe TBI is needed. Such a study should specifically address the issue of when it is safe to begin pharmacological therapy, deal agent, and dosing regimen in the patient with traumatic intracranial bleeding.

Whether the risks of pharmacological DVT prophylaxis are greater in specific traumatic intracranial lesions (contusions, subdural hematomas), than in others (small traumatic subarachnoid hemorrhage) needs to be explored. In addition, the indications, risks, and benefits of vena cava filters in severe TBI patients requires investigation.