Practice Management Guidelines for the Prevention of Venous Thromboembolism in Trauma Patients: The EAST Practice Management Guidelines Work Group

Abstract

The Eastern Association for the Surgery of Trauma (EAST) has taken a leadership role in the development of evidenced-based practice guidelines for trauma. 1 These original guidelines were developed by interested trauma surgeons in 1997 for the EAST Web site (http://www.east.org), where a brief summary of four guidelines was published. A revised, complete, and significantly edited practice management guidelines for the prevention of venous thromboembolism in trauma patients is presented herein. The step-by-step process of practice management guideline development, as outlined by the Agency for Health Care Policy and Research (AHCPR), has been used as the methodology for the development of these guidelines. 2 Briefly, the first step in guideline development is a classification of scientific evidence. A Class I study is a prospective, randomized controlled trial. A Class II study is a clinical study with prospectively collected data or large retrospective analyses with reliable data. A Class III study is retrospective data, expert opinion, or a case report. Once the evidence is classified, it can be used to make recommendations. A Level I recommendation is convincingly justifiable on the basis of the scientific information alone. Usually, such a recommendation is made on the basis of a preponderance of Class I data, but some strong Class II data can be used. A Level II recommendation means the recommendation is reasonably justifiable, usually on the basis of a preponderance of Class II data. If there are not enough Class I data to support a Level I recommendation, they may be used to support a Level II recommendation. A Level III recommendation is generally only supported by Class III data. These practice guidelines address eight different areas of practice management as they relate to the prevention and diagnosis of venous thromboembolism in trauma patients. There are few Level I recommendations because there is a paucity of Class I data in the area of trauma literature. We believe it is important to highlight areas where future investigation may bring about definitive Level I recommendations. RISK FACTORS FOR VENOUS THROMBOEMBOLISM AFTER INJURY I. Statement of the Problem A number of factors have been reported to increase the risk of venous thromboembolism (VTE) after injury. Because VTE prophylaxis is associated with complications, it is essential to identify subgroups of trauma patients in whom the benefit of VTE prophylaxis will outweigh the risk of its administration. This is important because the benefits from the different methods of prophylaxis are still unclear when compared with no prophylaxis. Because the literature is inconsistent, a systematic review is needed to produce the best available evidence. Below, we describe the results of a meta-analysis of the existing literature. The reader needs to remember the limitations of meta-analysis. In addition, the fact that a risk factor was not identified as significant in meta-analysis does not mean that this factor must be ignored. Absence of proof does not equal proof of absence. It only means that enough evidence does not exist and that further studies of high quality are needed. II. Process Three literature databases were searched (MEDLINE, EMBASE, and Cochrane Controlled Trials Register) for articles reporting risk factors of VTE. All articles were reviewed by two independent reviewers and a third reviewer in cases of disagreement. The review was prepared against predetermined screening criteria, and the articles were given a numerical quality score. From an initial broad research that identified 4,093 relevant titles, 73 articles met all the inclusion criteria and were finally accepted for meta-analysis. Pooled effect sizes (odds ratio [OR] and their 95% confidence intervals [CIs]) were estimated by the DerSimonian and Laird random-effects model. Shrinkage graphs were produced to display the effect size of each study and to compare with the overall model estimate. The heterogeneity among studies was tested by the Q statistic and p value for the χ2 test of heterogeneity. A level of significance at p < 0.05 was used for all comparisons. To include a risk factor for meta-analysis, three or more studies reported on the risk factor. Risk factors identified only in one or two studies were not included. The risk factors identified were treated as either dichotomous or continuous variables as appropriate. For instance, if three or more studies provided data on the incidence of VTE in patients who were older or younger than 55 years old, then the risk factor was "age > 55," a dichotomous variable. On the other hand, if three or more studies provided data on the age of patients with or without VTE by using only a mean and SD, the risk factor was simply "age," a continuous variable (Table 1).Table 1: Studies Reporting on Risk Factors of Venous Thromboembolism in Trauma PatientsIII. Recommendations Level I: Patients with spinal cord injuries or spinal fractures are at high-risk for venous thromboembolism after trauma. 2–12 Level II: 1. Older age is an increased factor for venous thromboembolism, but it is not clear at what exact age the risk increases substantially. 4,5,9,11,13,14 2. Increasing Injury Severity Score (ISS) and blood transfusion appear to increase the risk of venous thromboembolism, but this association is still unclear. 3,5,8,9,14,15 3. Traditional risk factors such as long bone fractures, 3–6,9–13,15–17 pelvic fractures, 3–5,9–12,15,18 or head injuries, 3–9,15 although significantly associated with a high risk of venous thromboembolisms in single-institution studies, were not found to be powerful risk factors on meta-analysis. IV. Scientific Foundation Risk factors As Dichotomous Variables The following variables were reported in three or more studies and were included in the meta-analysis: gender, 3,13,18,19 head injury, 3–9,15 long bone fracture, 3–6,9–13,16,17,19 pelvic fracture, 3–5,9–12,15 spinal fracture, 3–12 and spinal cord injury. 4,9–12 A number of studies included age as a risk factor, but the different cut-off points used in each study (age > 30, 40, 50, 55, etc.) did not allow an analysis of this variable. The only risk factors found to place the patient at higher risk for development of deep venous thrombosis (DVT) were spinal fractures (OR, 2.260; 95%; CI, 1.415–3.610) and, even greater, spinal cord injury (OR, 3.017; 95% CI, 1.794–5.381). No significant heterogeneity was reported among studies on the different risk factors. Although long bone fractures were not found to bear statistical significance on meta-analysis, at least one high-quality study 17 with a valid regression model and an adequate sample size found long bone fractures to be a significant risk factor for venous thromboembolism. Risk Factors As Continuous Variables Three continuous variables (i.e., age, 5,9,11,13,14 ISS, 3,5,9,11,14,15 and units of blood transfused 3,14,15) were reported in more than three studies and were included in the meta-analysis. Compared with patients without DVT, patients with DVT were significantly older (8.133 ± 1.504 [95% CI, 5.115–11.141]) years and had a significantly higher ISS (1.430 ± 0.747 [95% CI, 0.000–2.924]). The statistical difference in ISS was marginal, as shown by the lower limit of the 95% CI, and had minimal clinical significance. The difference of blood transfused between patients with and without DVT was not statistically significant (1.882 ± 2.815; 95% CI, −3.637–7.401), and no heterogeneity was reported among these studies. V. Summary The existing evidence supports the presence of two risk factors of posttraumatic VTE: spinal fractures and spinal cord injuries. Older age was an additional risk factor, but it was not clear at what exact age the risk increases substantially. Inadequate literature evidence exists to support that other frequently reported risk factors, such as long bone fractures, pelvic fractures, or head injuries, really increase the risk for VTE. However, a need exists for additional research in this area. In particular, adequate sized prospective studies should reevaluate the role of long bone fracture, pelvic fractures, head injuries, as well as specific age, blood transfusion, and ISS thresholds. V. Future Investigation Adequately sized studies should reevaluate the role of long bone fracture, pelvic fractures, and head injuries, as well as age, blood transfusion, and ISS thresholds and their association with the development of VTE after trauma. Large databases could be used to quantify risk using logistic regression profiles and could be the basis of specific prevention strategies. THE USE OF LOW-DOSE HEPARIN FOR DVT/PE PROPHYLAXIS I. Statement of the Problem The fact that DVT and pulmonary embolism (PE) occur after trauma is incontrovertible. The optimal mode of prophylaxis has yet to be determined. Low-dose heparin (LDH), given in doses of 5,000 units subcutaneously two or three times daily, represents one pharmacologic treatment modality for prophylaxis against DVT/PE. In contrast, LDH has not been shown to be particularly effective in preventing VTE in trauma patients. Three recent prospective trials demonstrated that LDH was no better in preventing DVT than no prophylaxis at all in patients with an ISS > 9. Sample sizes in these studies were small, and hence a type II statistical error cannot be excluded. The results of LDH use in trauma, with regard to PE, are even more vague. II. Process A MEDLINE review from 1966 to the present revealed several hundred articles related to the use of LDH in medical and general surgical patients. Only the nine articles related to the use of LDH in trauma patients were used for the following recommendations (Table 2).Table 2: Lose-Dose HeparinIII. Recommendations Level I: A Level I recommendation on this topic cannot be supported because of insufficient data. Level II: Little evidence exist to support the benefit of LDH as a sole agent for prophylaxis in the trauma patient at high-risk for VTE. 3,7,10,14,20–22 Level III: For patients in whom bleeding could exacerbate injuries (such as those with intracranial hemorrhage, incomplete spinal cord injuries, intraocular injuries, severe pelvic or lower extremity injuries with traumatic hemorrhage, and intra-abdominal solid organ injuries being managed nonoperatively), the safety of LDH has not been established, and an individual decision should be made when considering anticoagulant prophylaxis. IV. Scientific Foundation Heparin is a naturally occurring polysaccharide varying in molecular weight from 2,000 to 40,000. LDH augments the activity of antithrombin III, a potent, naturally occurring inhibitor of activated factor X (Xa) and thrombin, which produces interruption of both the intrinsic and extrinsic pathways. Low-dose heparin causes only minimal or no change in conventional clotting tests, such as the partial thromboplastin time. Studies on the use of LDH in trauma patients are inconclusive. In addition, many of these studies are single-institution studies with small sample sizes and lack randomization. These studies are summarized in Table 2. 7,20,21 Studies with larger sample sizes and randomization will be discussed herein. 3,5,10,14,17,22 Knudson et al. 3 reported on 251 patients in a cohort study who received LDH, a pneumatic compression device (PCD), or no prophylaxis. These authors failed to show any effectiveness with prophylaxis in most trauma patients, except in the subgroup of patients with neurotrauma in which PCD was more effective in preventing DVT than control. Upchurch et al. 14 compared 66 intensive care unit (ICU)-dependent trauma patients who received either LDH or no VTE prophylaxis. No significance difference was seen in VTE rates between the two groups. In this same study, the authors performed a meta-analysis of the current literature concerning the use of LDH in 1,102 trauma patients. This meta-analysis demonstrated no benefit of LDH as prophylaxis compared with no prophylaxis (10% vs. 7%;p = 0.771). Geerts et al. 17 randomized 344 trauma patients to receive low-molecular-weight heparin (LMWH) or LDH and found significantly fewer DVTs with LMWH than with LDH (31% vs. 44%, p = 0.014 for all DVT; and 15% vs. 6%, p = 0.012 for proximal DVT). This study had no control group. However, when compared with the predicted DVT rate if the study patients had not received prophylaxis, the risk reduction for LDH was only 19% for DVT and only 12% for proximal DVT, whereas the comparative risk reductions for LMWH were 43% and 65%, respectively. Napolitano et al. 10 used a serial ultrasound screening protocol for DVT in 437 patients who were given four types of prophylaxis (LDH, PCD, LDH and PCD, and no prophylaxis) according to their attending surgeon's preference. No significant difference was seen in DVT rates between groups (8.6%, 11.6%, 8.0%, and 11.9%, respectively). Velmahos et al. 5 looked at the use of LDH and PCD or PCD alone in 200 critically injured patients who were then followed with biweekly Doppler examinations to detect proximal lower extremity DVT. The incidence of DVT was 13% overall, and no difference was seen between the two groups. The majority (58%) of DVT developed in the first 2 weeks. In a meta-analysis conducted under the auspices of the Agency for Healthcare Research and Quality, Velmahos and colleagues 22 looked at all randomized controlled and nonrandomized studies on the use of LDH in trauma patients. The four randomized controlled studies on the use of LDH in trauma patients showed no difference in the incidence of DVT between those receiving LDH versus no prophylaxis (OR, 0.965; 95% CI, 0.360–2.965; vs. OR, 1.33; 95% CI, 0.360–2.965). V. Summary In summary, to date, LDH has very little proven efficacy in the prevention of VTE after trauma. Most studies on the use of LDH in trauma patients suffer from severe methodologic errors, poor study design, and small sample size, suggesting the possibility of a type II statistical error. VI. Future Investigation Enough accumulated data do not exist to support the use of LDH in a trial in high-risk trauma patients. Future studies should focus on the potential benefit of more efficacious agents such as low-molecular-weight heparin. THE ROLE OF ARTERIOVENOUS FOOT PUMPS IN THE PROPHYLAXIS OF DVT/PE IN THE TRAUMA PATIENT I. Statement of the Problem In 1983, Gardner and Fox 23 discovered a venous pump on the sole of the foot that consists of a plexus of veins that fills by gravity and empties on weightbearing, thus increasing femoral blood flow without muscular assistance. A mechanical device, the arteriovenous (A-V) foot pump, has been developed to mimic this effect of weightbearing. The major advantage of this system is that it only requires access to the foot, which enables its use in patients with Jones dressings, casts, or externally fixed limbs that previously were unsuitable for a PCD. One study has shown that the pulsatile action of the A-V foot pump increased venous blood flow velocity in the popliteal vein by 250%. 24 II. Process With the recent clinical introduction of the A-V foot pump, there is a paucity of relevant literature related to this subject. A MEDLINE review dating back to 1980 revealed 12 articles on A-V foot pumps, with 8 articles specifically related to the use of A-V foot pumps in the trauma patient. These eight studies were the basis for the recommendations below (Table 3).Table 3: A-V Foot PumpsIII. Recommendations Level I: A Level I recommendation for this topic cannot be supported because of insufficient data. Level II: A Level II recommendation for this topic cannot be supported because of insufficient data. Level III: A-V foot pumps may be used as a substitute for pneumatic compression devices in those high-risk trauma patients who cannot wear PCDs because of external fixators or casts and cannot be anticoagulated because of their injuries. It should be noted that in trauma patients, A-V foot pumps have not been shown to be as efficacious as PCDs and are associated with some significant complications. 12,25,26 IV. Scientific Foundation Most of the studies involving the use of A-V foot pumps are found in the orthopedic literature, and many of these series involve small numbers of patients. Although little has been documented on the effects of A-V footpumps on DVT in trauma patients, other beneficial effects have been observed. In 71 patients who had operations or casts for traumatic lower extremity injuries, Gardner and Fox 27 showed a significant decrease in pain, swelling, and measurement of compartment pressures in the affected extremities with the use of the A-V foot pumps. In the discussion to this article, the authors hypothesized that the increased blood flow seen with the pumps was because of hyperemia mediated by endothelial-derived relaxing factor (now thought to be nitric oxide) that was liberated by the endothelium secondary to sudden pressure changes, which could have been caused by the A-V pumps. This endothelial-derived relaxing factor release could encourage the opening of critically closed capillaries, enabling reabsorption of fluid, hence the decrease in compartment pressures. In addition, reports have been documented of A-V foot pumps improving arterial blood flow with the relief of ischemic rest pain. 28,29 In addition to preventing VTE, all of these proposed foot pump mechanisms of action may be potentially beneficial in healing extremity injuries. In a recent prospective randomized study by Knudson et al., 12 A-V foot pumps were one arm of a number of prophylactic measures (LMWH and PCDs were the other arms) used to prevent DVT in high-risk trauma patients. Of 372 patients enrolled in the study, the DVT rate was 5.7% for the A-V foot pumps, 2.5% for the PCDs, and 0.8% for the low-molecular-weight heparin as determined on follow-up serial duplex ultrasound. Of note, in 8 of 53 patients who wore foot pumps, severe skin changes, including blistering and wound problems, occurred. This required three patients to be removed early from the study. Spain et al. 25 compared the use of A-V foot pumps to PCDs in 184 consecutively injured patients. In this nonrandomized study, patients who could not receive a PCD because of lower extremity injuries were placed in A-V foot pumps. Overall, no significant difference was seen in DVT rates between the two with PCDs at and A-V foot pumps at The authors of this study that A-V foot pumps were a to PCDs when lower extremity fractures the use of et al. performed a randomized prospective trial A-V foot pumps with PCDs in high-risk orthopedic patients and followed with serial ultrasound. In patients, the overall incidence of DVT was in those with A-V foot pumps and in those with analysis of such a study was by the heterogeneity of the two groups and the fact that a number of patients received either or In study by et al. in a trauma of and patients, the A-V foot pumps were found to be and only of the a to that reported by et al. for V. Summary Only one clinical series in trauma patients A-V foot pumps with other of DVT prophylaxis. The results from this series were not definitive in of benefits of A-V foot pumps preventing DVT. However, a use of A-V foot pumps may exist in the high-risk trauma patient who has a to heparin because of injuries or who cannot have PCDs placed on lower extremities secondary to external fixators or large VI. Future randomized studies are needed A-V foot pumps to prophylactic measures in trauma patients at high risk for the development of DVT. THE USE OF IN THE OF DVT/PE I. Statement of the Problem The role of PCDs for prophylaxis against DVT has been and used in general patients, orthopedic patients, and trauma patients. the risk factor of PCDs have been shown to increase mean and femoral venous blood in the lower In addition, PCDs have been shown to have a effect on the that to the increases of inhibitor and the of In a number of prospective randomized studies, PCDs have been shown to the incidence of both DVT and the use of PCDs include the by which PCDs the efficacy of PCDs on the extremities or a lower extremity compared with both lower the of risk in PCDs and the of PCD that PCDs should be with this practice has not been used. of PCDs have been noted in case reports and have been associated with of the lower extremity which should be II. Process A MEDLINE from to the present produced a large number of articles on this articles to thromboembolism prevention were of these articles were to the following guidelines (Table Recommendations Level I: A Level I recommendation on this topic cannot be supported because of insufficient data. Level II: A Level II recommendation on this topic cannot be supported because of insufficient data. Level III: In a meta-analysis of studies on the benefit of PCDs in trauma patients, no benefit of the use of PCDs no prophylaxis was 22 In the of patients, PCDs may have some benefit in studies. IV. Scientific Foundation The factors that are to the basis of the of venous are of blood flow in the injury the of the and Scientific and clinical of PCDs that the of the effect on DVT prophylaxis from their to increase mean and femoral vein velocity and the and et al. venous velocity at the femoral vein using Doppler ultrasound in patients and in control In the control was increased from a mean velocity of at rest to with PCDs and with In patients, the was from a velocity of to In both of these the were statistically significant when compared with and were not further by the use of of blood flow velocity and of the PCDs revealed a association with and increased that a mechanical effect from of the Studies have in effects of In a study, et al. showed that times were not as a for study on in inhibitor and demonstrated a significant increase in an decrease in in patients pneumatic compression and a and role of PCDs in the of and found that activity to of This to have important clinical in that PCDs must be to in A recent study documented patients in whom PCDs have been but who than of the the which their important in the study by et al. was that there to be an decrease in activity when blood was in from the area of PCD This difference in and effects has important on the of PCDs on the to prevent DVT in the A paucity of studies exists specifically the use of PCDs in trauma patients with injuries. In a prospective study by Knudson et al., trauma patients received either PCDs and or This study showed a 12% rate of VTE in the PCD versus in the LDH which was not significantly This study did not that either of prevention or was better than no prophylaxis. et al. conducted a prospective, nonrandomized study of trauma patients with an ISS > who received either PCDs, LDH, or no prophylaxis, and who serial ultrasound screening for DVT at 5 and 10 after demonstrated a VTE rate of in the in the PCD and in the LDH group. No statistically significant difference was noted in VTE rates in the prophylaxis but a significant difference was seen in those who received prophylaxis versus no prophylaxis < and spinal patients, two to benefit from prophylaxis. Overall, risk reduction of VTE with prophylaxis was from to in patients and to in spinal patients. However, the of this study in that patients to receive no prophylaxis were to receive some of prophylaxis at the of the attending This may have the DVT rates for each prophylactic modality In a prospective Knudson et al. 3 compared PCD, LDH, and no prophylaxis. LDH PCD to any to trauma patients with injuries, except in the specific subgroup of patients with neurotrauma in which PCD was more effective in preventing DVT than control = In to the study by Knudson et al., et al., in a nonrandomized prospective study, looked at the incidence of VTE in a of patients with < patients received PCDs and did not because of lower extremity the receiving PCDs, four developed and developed DVT. In the not receiving prophylaxis, two developed and two developed DVT. Although the study was small, the in this study the efficacy of PCD even in severe patients. In a of orthopedic trauma patients with and pelvic fractures, PCDs were found to significantly those who had no prophylaxis vs. = In subgroup PCDs were only effective in the not in those with pelvic devices appear to be with minimal cases of pressure from a PCD have been and compartment have been reported with A potential of PCDs is intracranial pressure in patients with severe head injury. This was by et al. in 24 patients of who had and pressure after and of pneumatic The authors found no significant increase in or with the use of PCDs at any and that PCDs can be used in patients. In an evidenced-based meta-analysis by the Agency of Healthcare Research and on the incidence of DVT after trauma, Velmahos et al. 22 found that PCDs no benefit no prophylaxis in both randomized control studies (OR, 95% CI, and in nonrandomized controlled studies (OR, 95% CI, In study, Velmahos et al. 5 compared PCD, LDH, and a of PCD and LDH in a prospective study of 200 critically injured patients followed by Doppler ultrasound to detect proximal DVT. In all three the proximal DVT rate was the authors to any of the three prophylactic were in the high-risk patient. V. Summary studies the effectiveness of PCDs in trauma patients are Although the exact of action of PCDs is their effect is to be on a of factors is well and the system is these mechanisms are better and to specific the use of PCDs are VI. Future Investigation studies need to be performed specifically to the use of PCDs in trauma patients at risk for VTE. the efficacy of using the device on one lower extremity