Venous thromboembolic events in isolated severe traumatic brain injury.

OBJECTIVE: The purpose of this study was to investigate the effect of prophylactic anticoagulation on the incidence of venous thromboembolic events (VTE) in patients suffering from isolated severe traumatic brain injury (TBI).
MATERIALS AND METHODS: Retrospective matched case-control study in adult patients sustaining isolated severe TBI (head AIS ≥3, with extracranial AIS ≤2) receiving VTE prophylaxis while in the surgical intensive care unit from 1/2007 through 12/2009. Patients subjected to VTE prophylaxis were matched 1:1 by age, gender, glasgow coma scale (GCS) score at admission, presence of hypotension on admission, injury severity score, and head abbreviated injury scale (AIS) score, with patients who did not receive chemical VTE prophylaxis. The primary outcome measure was VTE. Secondary outcomes were SICU and hospital length of stay (HLOS), adverse effects of anticoagulation, and mortality.
RESULTS: After propensity matching, 37 matched pairs were analysed. Cases and controls had similar demographics, injury characteristics, rate of craniotomies/craniectomies, SICU LOS, and HLOS. The median time of commencement of VTE prophylaxis was 10 days. The incidence of VTE was increased 3.5-fold in the controls compared to the cases (95% CI 1.0-12.1, P=0.002). The mortality was higher in patients who did not receive anticoagulation (19% vs. 5%, P=0.001). No adverse outcomes were detected in the anticoagulated patients.
CONCLUSION: Prophylactic anticoagulation decreases the overall risk for clinically significant VTE in patients with severe isolated TBI. Prospective validation of the timing and safety of chemical VTE prophylaxis in these instances is warranted.

BACKGROUND

Venous thromboembolic events (VTE) are common following traumatic insults.[1-6] Without appropriate intervention, deep venous thrombosis (DVT) may result in pulmonary emboli (PE) and death.[578] Previous investigations have demonstrated independent associations between traumatic brain injury (TBI) and VTE in victims of multisystem injury.[25910] Nevertheless, studies scrutinizing the clinical effects of VTE in isolated severe TBI are scarce. Thus we set out to examine the incidence of VTE in victims of isolated severe TBI undergoing prophylactic anticoagulation compared to those with no prophylactic anticoagulation and to compare in-hospital outcome measures in these cohorts.

MATERIALS AND METHODS

After Institutional Review Board approval the trauma registry of the Los Angeles County and University of Southern California (LAC+USC) Medical Center, an academic urban Level 1 trauma center, was reviewed to identify all adult patients (age ≥18 years) from 1/2007 to 12/2009, admitted to the surgical intensive care unit (SICU) after blunt-isolated severe TBI. Isolated severe TBI was defined by a head abbreviated injury scale (AIS) ≥3 with chest, abdomen, and extremity AIS ≤2. Patients who expired or experienced SICU length of stay less than 48 hours were excluded.

Patient demographic and clinical characteristics extracted from the trauma registry included gender, age, systolic blood pressure (SBP) at admission, Glasgow Coma Scale (GCS) score at admission, Injury Severity Score (ISS), head AIS, SICU length of stay (SICU LOS), hospital length of stay (HLOS), and mortality. Patient electronic charts, SICU electronic charts, and radiology reports were reviewed for the commencement day of anticoagulation therapy, diagnostic modality utilized, VTE incidence, and causes of mortality.

At LAC+USC, VTE diagnostic work-up is performed on clinical suspicion. The diagnosis of DVT is based on duplex ultrasound or computed tomography angiography (CTA). The diagnosis of pulmonary embolism is based on CTA of the pulmonary artery (CTPA).

The prophylactic anticoagulation utilized during the study period was provided with unfractionated heparin (Heparin Sodium, Braun Medical Inc., Irvine, CA) at 5000 units subcutaneously three doses daily or enoxaparin sodium (Lovenox®, Sanofi-Aventis, Bridgewater, NJ) at 30 mg subcutaneously twice daily. VTE prophylaxis was commenced when neurosurgical service cleared the patient for the intervention. According to institutional policy, sequential pneumatic compressive devices were universally applied to lower extremities.

Statistical analysis

The primary outcome measure was VTE and the primary variable of interest was prophylactic anticoagulation therapy. Secondary outcomes of interest were the ICU LOS, HLOS, and mortality. For analysis purposes, several continuous variables were analyzed as dichotomous variables using clinically relevant cut-points (SBP <90 mmHg, GCS ≤8, and ISS ≥16). Because the number of confounders was large in comparison with the number of events, cases receiving VTE prophylaxis were matched in a 1:1 ratio to controls that did not receive prophylactic anticoagulation therapy using propensity score matching. Variables included in the propensity score model were age, gender, ISS, GCS, hypotension (SBP <90 mmHg), and head AIS. Propensity score (predicted probability of receiving prophylactic anticoagulation) were calculated for all patients using binary logistic regression.[11] Each patient receiving prophylactic anticoagulation was matched to a patient who was not subjected to prophylactic anticoagulation within a 0.0135 caliber of propensity without replacement. The caliber was equal to one-quarter of an standard deviation (SD) of the logit of the propensity score.[12] Anticoagulated patients for whom no suitable match could be found were excluded from the analysis.

Demographics and clinical characteristics between the matched cohorts were compared using univariate analysis. The differences between the cohorts were tested for significance using the McNemar test for categorical variables and paired Student ‘t’ test or Wilcoxon signed rank test for continuous variables when appropriate. Values are reported as percentage for categorical variables and as mean±SD or median and range for continuous variables.

The risk for VTE and mortality between the groups were analyzed and the odds ratio (OR) and 95% confidence interval (CI) were derived. The SICU and HLOS between the matched cohorts were also analyzed and mean difference and 95% CI were calculated.

The statistical analysis was performed using the Statistical Package for Social Science (SPSS Windows©) version 12.0 (SPPS Inc., Chicago, IL).

RESULTS

During the 3-year study period, a total of 416 patients met study inclusion criteria. Of these 41 patients (10%) received prophylactic anticoagulation during their SICU stay [Figure 1]. After propensity matching, 37 matched pairs were available for analysis [Figure 1]. The average age of matched patients was 47±16 years, 90% were male. At admission, 1.4% of the patients were hypotensive, 43% had a GCS ≤8, and 64% had an ISS ≥16. Overall, 46% of patients had a head AIS 3, 42% head AIS 4, and 12% head AIS 5. A total of 17% of the patients had a craniotomy/craniectomy. The demographics and clinical characteristics before and after matching are summarized in Table 1. There was no statistically significant difference in overall ISS or head AIS between patients with isolated TBI who received chemical prophylaxis vs. no prophylaxis. The discrepancies between the cases and controls were even less marked after propensity matching [Table 1]. Overall, 34% of our study population had a diagnostic study performed for VTE, 60% of those patients suffered a VTE. Overall, the incidence of clinically significant VTE was 20%. Patients not receiving prophylactic anticoagulation experienced a VTE at a significantly higher rate [30% vs. 11%; (OR 3.5, 95% CI 1.0-12.1, P=0.002)] [Table 2]. None of the patients who were subjected to chemical VTE prophylaxis experienced any clinically obvious VTE prior to initiation of anticoagulation. Mean time from hospital admission to initiation of prophylactic anticoagulation was 10 days (±6 days) [median 10 days (3-30 days)]. There was no statistical difference in the time of diagnosis for VTE between patients who received versus those who did not receive prophylactic anticoagulation (20±8 days vs. 18±8 days, P=0.77) [Table 1]. In the anticoagulated group, one patient experienced pulmonary embolism and three instances of DVT were documented. In the nonanticoagulated cohort, three patients had PE and eight DVTs.

Figure 1

Study outline, Abbreviations: TBI=Traumatic brain injury, VTE=Venous tromboemolic event

Table 1

Demographic and clinical characteristics

Table 2

Outcomes between the non-anticoaglated vs. Anticoagulated patients

When the secondary outcomes were compared between the prophylactically anticoagulated patients and their nonanticoagulated counterparts there was no significant difference in SICU length of stay (13±8 days vs. 16±30 days, P=0.59) or the hospital length of stay (26±14 days vs. 21±30 days, P=0.352). A total of nine (17%) patients died during their hospital stay. Mortality was significantly higher in patients who did not receive anticoagulation therapy (19% vs. 5%, P=0.001), but only one case was due to PE [Table 3]. There were no adverse effects of the prophylactic anticoagulation in our study population.

Table 3

Cause of death in the matched population (n=9)

DISCUSSION

The fact that VTE and pulmonary embolism occurs after trauma is incontrovertible. The reported incidence of VTE after trauma varies from 7 to 58% depending upon the demographics of the study population, the nature and severity of the injuries considered, the method of detection of VTE (routine screening or symptomatic investigation), and the type of VTE prophylaxis used.[12461013] Without prophylaxis, patients suffering from multisystem or major trauma have a VTE risk exceeding 50%,[5814] and in this population PE is the third leading cause of death in those who survive beyond the first day.[57] Several factors, including age, increasing injury severity score, long bone fractures, pelvic fractures, spinal cord injuries, and head injuries, have been independently associated with increased risk for VTE.[2-51015] After reviewing 1,602 DVT cases from the American College of Surgeons National Data Bank, Knudson and colleagues found that a head AIS ≥3 was an independent risk factor for development of DVT in trauma patients (adj. OR 1.24; 95% 1.05-1.46, P=0.0125).[2]

The rate of VTE in TBI patients has been reported to be as high as 20-25% when medical prophylaxis is not used or is delayed.[1617] In studies where low-molecular heparin (LMWH) was initiated 24 hours after head injury, the incidence of VTE ranged between 0 and 4%.[1819] Dudley and colleagues reported a 7% rate of VTE in patients with moderate to severe TBI (GCS 3-12) who received LMWH within 48-72 h.[20] In our cohort, the rate of VTEs was 30% in the non-anticoagulated group and 11% in the anticoagulated group of patients (P=0.002).

One reason for the higher rate of VTE in our study compared to the previous reports mentioned[18-20] could be explained by the fact that those studies did not stratify their patients based on the severity of their TBI. Therefore, some of these studies may have included patients with a mild to moderate injury (GCS 9-15) who were mobilized earlier and thus less susceptible to VTE. Another explanation for the lower rate of VTE compared to ours could be the difference in the commencement of VTE prophylaxis between our study and the previous reports.[18-20] Reiff and colleagues reported an increased risk of DVT in TBI patients as time to initiation of VTE prophylaxis increased, with a 3.6% risk when anticoagulation was started within the first 24h, a 4.5% risk when started within 24-48 h, and a 15.4% risk if started beyond 48 h.[21]

Early VTE prophylaxis is a concern for the possible progression intracranial hemorrhage in TBI patients. When LMWH was commenced at 24 h post-injury, Norwood and colleagues reported worsening of intracranial hemorrhage in 4% and 9% among TBI patients who had not undergone an operation versus those subjected to craniotomy/craniectomy, respectively.[19] In 2003, Kleindienst et al. reported a case series of 940 neurosurgical patients, including 344 patients with TBI who were treated with LMWH within 24 h of admission or surgery. Nine (3.2%) of the patients in that study had progression of their intracranial hematoma and, of these, eight (88%) had subsequent reoperation.[18] However, these studies failed to stratify their patients by the severity of the TBI. Another concern about the timing of initiation of VTE prophylaxis is the time course of TBI-coagulopathy which may occur as late as 5 days after the injury with a prolonged duration (>72 h) in 30% of patients.[22] In our cohort, the mean time for commencement of VTE prophylaxis was 10 days with a range of 3-30 days. We did not see any subsequent increase in intracranial hemorrhage in our patients who were anticoagulated.

The presence or absence of VTE prophylaxis did not make a difference in the time to VTE occurrence in our study population, with the great majority of patients receiving their diagnosis in the first 3 weeks (18±8 days and 20±8 days, P=0.772) after admission. This finding could be explained by the fact that we investigated for possible VTE based on clinical suspicion.

To the best of our knowledge, this is the first study examining VTE incidence, safety, and risk factors associated with prophylactic anticoagulation in victims of isolated severe traumatic brain injury. However, there are several limitations to our study primarily due to its retrospective design. Our sample size was small due to very specific inclusion criteria applied. The decision and timing for inititation of VTE prophylaxis was at the discretion of attending trauma surgeon in concert with the neurosurgical service, and could potentially be a source of selection bias. Finally, no screening for VTE was performed and therefore the incidence of VTEs in our study cohort is likely higher than in an unscreened severe TBI population. However, despite these limitations, this study contributes to literature pertinent to the incidence and outcomes of VTE in patients with isolated severe TBI.

CONCLUSIONS

Prophylactic anticoagulation decreases the overall risk for clinically significant VTE in patients with severe isolated TBI. Prospective validation of the timing and safety of chemical VTE prophylaxis in these instances is warranted.