Deep Venous Thrombosis and Thromboembolism in Patients With Cervical Spinal Cord Injuries
Dhall, Sanjay S. MD*; Hadley, Mark N. MD‡; Aarabi, Bizhan MD, FRCSC§; Gelb, Daniel E. MD¶; Hurlbert, R. John MD, PhD, FRCSC║; Rozzelle, Curtis J. MD#; Ryken, Timothy C. MD, MS**; Theodore, Nicholas MD‡‡; Walters, Beverly C. MD, MSc, FRCSC‡,§§
*Department of Neurosurgery, Emory University, Atlanta, Georgia
‡Division of Neurological Surgery, and
#Division of Neurological Surgery, Children’s Hospital of Alabama, University of Alabama at Birmingham, Birmingham, Alabama
§Department of Neurosurgery, and
¶Department of Orthopaedics, University of Maryland, Baltimore, Maryland
║Department of Clinical Neurosciences, University of Calgary Spine Program, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
**Iowa Spine & Brain Institute, University of Iowa, Waterloo/Iowa City, Iowa
‡‡Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona
§§Department of Neurosciences, Inova Health System, Falls Church, Virginia
Correspondence: Mark N. Hadley, MD, FACS, UAB Division of Neurological Surgery, 510 – 20th Street South, FOT 1030, Birmingham, AL 35294-3410. E-mail: firstname.lastname@example.org
ABBREVIATIONS: ASCI, acute spinal cord injury
DVT, deep venous thrombosis
IVC, inferior vena cava
LMWH, low molecular weight heparins
PE, pulmonary embolism
SCI, spinal cord injury
UFH, unfractionated heparin
VOP, venous occlusion plethysmography
VTE, venous thromboembolism.
* Prophylactic treatment of venous thromboembolism (VTE) in patients with severe motor deficits due to spinal cord injury is recommended.
* The use of low molecular weight heparins, rotating beds, or a combination of modalities is recommended as a prophylactic treatment strategy.
* Low dose heparin in combination with pneumatic compression stockings or electrical stimulation is recommended as a prophylactic treatment strategy.
* Low dose heparin therapy alone is not recommended as a prophylactic treatment strategy.
* Oral anticoagulation alone is not recommended as a prophylactic treatment strategy.
* Early administration of VTE prophylaxis (within 72 hours) is recommended.
* A 3-month duration of prophylactic treatment for deep vein thrombosis (DVT) and pulmonary embolism (PE) is recommended.
* Vena cava filters are not recommended as a routine prophylactic measure, but are recommended for select patients who fail anticoagulation or who are not candidates for anticoagulation and/or mechanical devices.
* Duplex Doppler ultrasound, impedance plethysmography, venous occlusion plethysmography, venography, and the clinical examination are recommended for use as diagnostic tests for DVT in the spinal cord injured population.
DVT and PE collectively considered as VTE are problems frequently encountered in patients who have sustained cervical spinal cord injuries. Several means of prophylaxis and treatment are available, including anticoagulation, pneumatic compression devices, and vena cava filters. In 2002, the guidelines author group of the Joint Section on Disorders of the Spine and Peripheral Nerves of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) produced a medical evidence-based guideline on this important topic.1 The purpose of this current evidence-based review is to update, evaluate, and rank the literature on the methods of prevention, identification, and treatment of VTE complications in patients following acute cervical spinal cord injury published since 2002.
A National Library of Medicine (PubMed) computerized literature search from 1966 through 2011 was performed using Medical Subject Headings in combination with “spinal cord injury”: “deep venous thrombosis” “pulmonary embolism” and “thromboembolism.” The search was limited to human studies reported in the English language. This resulted in 599 citations. Duplicate references, reviews, letters, and tangential reports were discarded. The bibliographies of these citations were analyzed for additional potential contributions. Finally, the author group found 45 citations describing the diagnosis, prophylaxis or treatment of thromboembolic disease in adult spinal cord injured patients make up the basis for this guideline and are summarized in Evidentiary Table format (Table). Supporting references included 4 evidence-based reviews on VTE prophylaxis and treatment in a variety of patient populations. Finally, several series dealing with VTE in general trauma patients with results germane to a discussion of spinal cord injured patients are included in the bibliography as supporting documents.
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The incidence of thromboembolic complications in the untreated spinal cord injury (SCI) population is high. Depending upon injury severity, patient age, and the methods used to diagnose a thromboembolism, the incidence of thromboembolic events ranges from 7% to 100% in reported series of patients receiving either no prophylaxis or inadequate prophylaxis.2-14 Substantial morbidity and mortality has been associated with the occurrence of DVT and PE events in the SCI population.15,16,55-57
Prophylactic therapy has been shown to be effective for the prevention of DVT and PE. In a small randomized study, Becker et al17 demonstrated that the use of rotating beds during the first 10 days following SCI decreased the incidence of DVT and provided Class I medical evidence on this subject. Four of 5 control patients were diagnosed with DVT (by fibrinogen screening) compared to 1 of 10 treated patients. The use of low dose heparin (5000 units given via subcutaneous injection twice or 3 times daily) has been described by several authors.3,6,7,12,18-20 Hachen19 published the results of a retrospective historical comparison of low dose heparin vs oral anticoagulation in a group of 120 SCI patients. He found a lower incidence of thromboembolic events in the low dose heparin group compared to the oral anticoagulation group. In 1977, Casas et al18 reported the results of a prospective assessment of low dose heparin in SCI patients. They administered heparin for a mean period of 66 days in 18 SCI patients and noted no thromboembolic events as detected by clinical examination. Watson reported a lower incidence of thromboembolic events with the use of low dose heparin when compared to no prophylaxis in a retrospective historical cohort study.20 Frisbie and Sasahara, however, found that low dose heparin did not affect the incidence of DVT in a prospective study of 32 SCI patients compared to treatment with twice daily physical therapy alone. These authors felt that the lack of effect was due to the very low incidence of DVT in their control group compared to other series because of the aggressive physical therapy paradigm employed in their patients. Although they performed screening venous occlusion plethysmography (VOP) with confirmatory venography weekly, the incidence of DVT was only 7% in both groups, suggesting that the treatments were equivalent in their study.4 This low incidence of DVT is substantially lower than that reported by 2 separate groups of investigators a decade later.6,7 In 1992, Kulkarni et al reported the much higher incidence of DVT (26%) and of PE (9%) in a group of 100 SCI patients prospectively treated with low-dose heparin.7 In 1993, Gunduz et al reported a 53% incidence of DVT confirmed by venography in 31 patients they managed with SCI treated with low dose heparin.6 In a study published in 1999, Powell et al noted that the incidence of DVT in 189 SCI patients receiving prophylaxis was significantly lower than that identified in SCI patients who did not receive prophylaxis, 4.1% vs 16.4%, respectively. Their comparative study provides supportive Class II medical evidence in favor of DVT prophylaxis. They reported that DVT in the prophylaxis group occurred in patients who received low dose heparin alone.12
Several studies have demonstrated that better prophylactic therapies than low dose heparin exist.5,9,21 Green et al5 published a randomized controlled study comparing low dose vs adjusted dose heparin (dose adjusted to APTT 1.5 times normal) in SCI patients. They found that patients treated with adjusted dose heparin had fewer thromboembolic events (7% vs 31%) during the course of their 10-week study, but had a higher incidence of bleeding complications. Merli et al21 in 1988 reported their findings of the additive protective effects of electrical stimulation in combination with low dose heparin, heparin alone, and placebo in 48 SCI patients treated for 4 weeks duration. In this Class I prospective, randomized medical evidence trial, they found that the heparin therapy alone group had a similar incidence of DVT compared to the placebo group. The combination of low dose heparin and electrical stimulation significantly decreased the incidence of DVT (1 of 15 patients compared to the other 2 treatment groups (8/16 low dose heparin alone, and 8/17 placebo, P < .05), providing Class I medical evidence on this issue.21 In 1992, this same group reported that heparin in combination with pneumatic stockings was equal to the effectiveness of heparin plus electrical stimulation.9 The heparin in combination with electrical stimulation group and the placebo group for this comparison were a historical cohort, rendering the medical evidence provided Class III. Winemiller et al22 studied a large series of 428 SCI patients with a multivariate analysis and found that the use of pneumatic compression devices for 6 weeks duration was associated with a significant decrease in thromboembolic events (odds ratio of 0.5 [95% CI 0.28-0.90]). Low dose heparin treatment seemed to have a protective effect as well; however, the effect of heparin alone was not statistically significant.
Recently, low molecular weight heparins (LMWH) have been studied as prophylactic therapy for thromboembolism in SCI patients. Green et al23 treated a series of SCI patients with 8 weeks of LMWH (tinzaparin) and compared the results with a historical cohort of patients treated with low dose or adjusted dose heparin. They found that the use of LMWH compared favorably with the use of either heparin dosing regimen in terms of fewer thromboembolic events, (16 events in 79 patients in the heparin group vs 7 events among 68 patients in the LMWH group, P = .15). Patients treated with LMWH had a significant decrease in bleeding complications (9 of 79 in the heparin group vs 1 of 68 in the LMWH group, P = .04).23 More recently, Harris et al24 performed a retrospective study of LMWH (enoxaparin) administration in a series of 105 patients with spinal injuries. Forty of their 105 patients suffered neurologically complete injuries. No patient exhibited clinical or ultrasound evidence of DVT and no patient suffered a PE treated with LMWH.24 Roussi et al25 reported a 9% incidence of DVT in a study involving 69 SCI patients receiving LMWH, testimony to the fact that no prophylactic therapy is 100% effective.
In 2003, the Spinal Cord Injury Thromboprophylaxis Investigators reported their study that randomized 476 acute SCI patients to unfractionated heparin (UFH) plus intermittent pneumatic compression or to enoxeparin as VTE prophylaxis strategies. The study was sponsored by the enoxeparin manufacturer. All but 107 patients were excluded from analysis due to “protocol deviations, bleeding and/or other adverse clinical events, thrombocytopenia and/or other adverse laboratory findings, withdrawal of consent, and intercurrent illness.” Though they found no significant difference in the incidence of thromboembolism between the treatment groups (63.3% vs 65.5%, respectively), they did note a significantly lower incidence of PE in the enoxaparin group (5.2%) vs the UFH + IPC group (18.4%). Due to the high exclusion rate, the medical evidence provided by this study is downgraded to Class III.26
In 2003, this same group prospectively examined the incidence of VTE in SCI patients in the rehabilitation phase (2 weeks after injury) who received either enoxaparin or UFH for 6 weeks. Of the 172 patients in their study, they excluded 53 due to “protocol deviations, bleeding and/or other adverse clinical events, thrombocytopenia and/or other adverse laboratory findings, withdrawal of consent, and intercurrent illness.” In the remaining patients, they found a lower incidence of thromboembolic complications in patients treated with enoxeparin (21.7% vs 8.5%; P = .052). Due to the high exclusion rate, the medical evidence provided by this study is downgraded to Class III.27
In 2004, Hebbeler and colleagues28 compared once daily dosing (40 mg) of enoxaparin to twice daily (30 mg each) dosing and found no significant difference in the incidence of thromboembolic complications among SCI patients in the rehabilitation setting. In 2005, Green et al29 compared the incidence of DVT in SCI patients treated from 1992 to 1995 to SCI patients they treated from 1999 to 2003, and found a significant decrease from 21% in the group of patients treated in the early 1990s compared to 7.9% in the latter series managed in the early 2000s. They concluded that the decline in the incidence of venous thromboembolism in their 2 patient series coincided with their transition from unfractionated heparin to LMWH used for prophylaxis. In 2007, Slavik et al30 performed a retrospective cohort study comparing enoxaparin to dalteparin in 135 patients with orthopedic trauma and/or spinal cord injury (73 with SCI). They found that the incidence of VTE was 1.8% and 9.7% in the enoxaparin and dalteparin patients, respectively, but reported that this difference was not statistically significant (P = .103).30 In 2010, Arnold et al31 performed a retrospective cohort study comparing unfractionated heparin to enoxeparin in 476 trauma patients, including 24 with spinal cord injury. Proximal lower extremity DVTs were detected in 16 patients in the enoxaparin group (6.75%) and in 17 patients in the UFH group (7.11%). Among the 24 SCI patients, however, the authors found the incidence of DVT in the enoxeparin group to be 36.4% compared to 15.4% in the UFH treated group (P = .357). The authors concluded that UFH was equally effective as enoxeparin as prophylaxis against DVT in their study, and far less expensive.31 These 4 retrospective studies offer Class III medical evidence on the use of UFH, dalteparin and enoxeparin as prophylaxis for DVT28-31; however, the study populations were heterogeneous and difficult to compare. Many patients in these various studies were managed with chemical prophylaxis and other prophylactic modalities, yet others were managed with chemical prophylaxis alone; therefore, conclusions regarding these agents as stand-alone therapy cannot be made.
Prophylaxis: Inferior Vena Cava Filters
The use of inferior vena cava (IVC) filters as prophylactic devices for thromboembolism has been advocated.32-35 Wilson et al35 placed caval filters in 15 SCI patients who were concurrently treated with either low dose heparin or pneumatic stockings. None suffered a PE during a 1-year follow-up period. The reported 1-year patency rate of the IVC was 81%. The authors noted that their results are superior to those from a historical cohort of 111 patients treated without IVC filters.35 Seven of the cohort patients suffered a PE; however, 6 of the 7 were not receiving any prophylaxis at the time of their PE. The single patient they described who had a PE while receiving DVT prophylaxis suffered a gunshot blast injury to the spine.35 Khansarinia and colleagues33 described a historical cohort study of 108 general trauma patients treated with prophylactic IVC filters. None of these patients suffered a PE. They compared this group to another historical cohort of 216 patients treated (apparently) with either low dose heparin or pneumatic compression devices prior to the use of IVC filters. Thirteen of these 216 suffered a PE, 9 of which were fatal.33 The mortality among the filter treatment group was lower than the mortality of the control group, but the difference was not significant (16% vs 22%).33 Tola et al36 have shown that percutaneous IVC filter placement in the intensive care unit setting is safe and is less costly than IVC filter placement in the operating room or the radiology suite. These authors suggest that IVC interruption is an effective means to prevent PE.
The placement of IVC filters is not without complications. Balshi et al, Kinney et al, and others have described distal migration, intraperitoneal erosion, and symptomatic IVC occlusion in patients with SCI treated with IVC filters.37-39 Balshi et al37 have hypothesized that quadriplegic patients are at higher risk for complications from IVC filter placement due to loss of abdominal muscle tone, as well as their requisite use of the “quad cough” maneuver.
In 2009, Gorman and colleagues40 performed a retrospective chart review of 114 patients with SCI, 47% of whom were treated with prophylactic IVC filter placement. All SCI patients received either LMWH or heparin prophylaxis. The IVC filter group had significantly more DVTs (20.4%) when compared to the group without filters (5.4%). Interestingly, only 1 patient suffered from PE; that patient had received a prophylactic IVC filter.
Timing and Duration of Prophylaxis
The vast majority of VTE events appear to occur within the first 2 to 3 months following injury. Naso described his experience with 4 patients with PE in a group of 43 SCI patients. All 4 PE events were documented within 3 months of injury.41 Perkash et al reported an 18% incidence of thromboembolism in a series of 48 patients with acute spinal cord injury and 2 patients with transverse myelitis. Only 1 patient had a new onset PE 3 months after injury; 2 other patients had recurrent PE 3 months after injury due to existing DVT.11 Lamb et al8 determined that the risk of thromboembolic events in their series of 287 SCI patients was 10%. The vast majority of events occurred within the first 6 months following injury. Twenty-two of 28 events they documented occurred within the first 3 months of injury. El Masri and Silver3 reported 21 documented events of PE in a series of 102 spinal injured patients. Twenty of 21 events occurred within the first 3 months following SCI. A pulmonary embolism occurred in a patient with a history of PE whose therapeutic anticoagulation was discontinued for gallbladder surgery.3 DeVivo et al42 described a 500-fold risk of dying from PE in the first month following acute SCI, compared to age- and gender-matched non-injured patients. This risk decreased with time, but remained approximately 20 times greater than that for normative controls 6 months following SCI.42 McKinley et al43 studied chronic spinal injured patients in a rehabilitation center setting and found an incidence of DVT of 2.1% in the first year following injury. This incidence dropped to between 0.5% and 1% per year thereafter.43 The collective data from these 6 studies provide confirming evidence that the great majority of thromboembolic events (DVT and PE) occur within the first 3 months after acute SCI and is considered Class II medical evidence.3,8,11,41-43 Prolonged prophylactic anticoagulation therapy is not without risk, and is associated with bleeding complications.5,23 The vast majority of studies addressing prophylactic treatment for DVT and PE have utilized treatment courses of 8 to 12 weeks duration with success. In 2002, Aito and colleagues44 studied 275 patients admitted to their institution with acute SCI (ASCI) who were screened for DVT with color Doppler ultrasonography at admission and at 30 to 45 days, or when clinically indicated. They found only 2% of patients admitted within 72 hours had DVT compared to 26% among patients admitted between 8 and 28 days after injury. Remarkably, none of the delayed admission group patients were prophylactically treated with sequential compression devices prior to admission. These authors provide Class II medical evidence that the early application of both chemical and mechanical prophylaxis reduces the incidence of DVT in patients with acute SCI.44
In 2009, Ploumis et al45 surveyed 25 spine surgeons to obtain a consensus on the use of pharmacologic thromboprophylaxis following spinal injury. The consensus was that postoperative pharmacologic thromboprophylaxis was unnecessary in patients with cervical spinal injuries without SCI; however, it was recommended in instances of cervical spine trauma with SCI or patients treated with anterior thoracolumbar procedures, irrespective of SCI. It was recommended that pharmacologic thromboprophylaxis be initiated preoperatively as soon as possible in patients with SCI and in cases requiring a delay in surgical treatment. Pharmacologic prophylaxis was recommended to be administered for at least 3 months post-injury.45
For these reasons, it is recommended that prophylactic treatment be continued for 8 to 12 weeks in spinal cord injury patients without other major risk factors for DVT and PE. Prophylactic treatment may be discontinued earlier in patients with useful motor function in the lower extremities, as these patients appear to be at less risk for DVT and PE.10,16
The diagnosis of DVT in various studies has been made based on the clinical examination, Doppler ultrasound examination, impedence plethysmography, venous occlusion plethysmography (VOP), venography, fibrinogen scanning, or by D-Dimer measurement.2-7,10,11,17,19,21,41,42,46-50 There is no established “gold standard” examination for DVT. Venography has been considered the best test, but is too inaccurate, is not possible in all patients, is invasive, and expensive.51 Gunduz et al6 report a 10% incidence of adverse effects from venography including post-venographic phlebitis and allergic reactions. Doppler ultrasound examination and VOP are both less invasive, less expensive, and more broadly applicable.12,51 The sensitivity and specificity of these examinations when compared with venography has been generally reported to range from 80% to 100%. Chu et al52 compared Doppler ultrasound and VOP with the clinical examination and found all 3 to agree 100% of the time in a small series of 21 patients. Perkash and colleagues11 studied a series of 48 SCI patients with daily physical examinations and weekly VOP. They found that the sensitivity of the clinical examination compared to VOP was 89%. The specificity was 88%, the negative predictive value was 97%, and the positive predictive value was 62% in their study. Other authors have described the increased sensitivity of fibrinogen scanning and the use of D-Dimer measurements for the diagnosis of DVT.25,53 Increased sensitivity is associated with decreased specificity. For example, Roussi et al25 reported 100% sensitivity and 100% negative predictive value with D-Dimer determinations compared to Doppler ultrasound and the clinical examination. The specificity of D-Dimer was only 34%, and the positive predictive value was only 13%. Similarly, Todd et al53 found that fibrinogen scanning was positive in all 20 patients studied in a prospective fashion. However, the diagnosis of DVT was confirmed by another test in only half of the cases. Akman and colleagues came to similar conclusions when they studied the D-Dimer assay in 68 patients with stroke, spinal cord injury, and head injury. The specificity and positive predictive value were low, at 55.3% and 48.7%, respectively. However, they reported the test to be 95.2% sensitive, with a 96.2% negative predictive value, suggesting it has value for excluding a diagnosis of VTE.54
Overall, no single test is completely applicable, accurate, and sensitive for the detection of DVT in the SCI patient population. Furthermore, a substantial number of patients who suffer from PE are found to have negative lower extremity venograms. The Consortium for Spinal Cord Medicine has recommended the use of ultrasound for the study of patients with suspected DVT, and venography when clinical suspicion is strong and the ultrasound examination is negative.16 In 2008, the American College of Chest Physicians recommended serial Doppler ultrasonography in spinal cord injury patients. Based upon the reported literature on this subject, Class III medical evidence suggests that each of these diagnostic tests for DVT has merit, each with limitations as noted above.
Thromboembolic disease is a common occurrence in patients who have sustained a cervical spinal cord injury and is associated with significant morbidity. Class I medical evidence exists demonstrating the efficacy of several means of prophylaxis for the prevention of thromboembolic events. Therefore, patients with SCI should be treated with a regimen aimed at VTE prophylaxis.
Although low dose heparin therapy has been reported to be effective as prophylaxis for thromboembolism in several Class III studies, other Class I, Class II, and Class III medical evidence indicates that better alternatives than low dose heparin therapy exist. These alternatives include the use of low molecular weight heparin, adjusted dose heparin, or anticoagulation in conjunction with rotating beds, pneumatic compression devices or electrical stimulation. Oral anticoagulation alone does not appear to be as effective as these other measures used for prophylaxis.
There appears to be a DVT prophylaxis benefit to early anticoagulation in acute spinal cord injury patients. Class II medical evidence supports beginning mechanical and chemical prophylaxis upon admission after SCI and holding chemical prophylaxis 1 day prior to and 1 day following surgical intervention.
The incidence of thromboembolic events appears to decrease over time and the prolonged use of anticoagulant therapy is associated with a definite incidence of bleeding complications. There are multiple reports of the beneficial effects of the prophylaxis therapy for 6 to 12 weeks following spinal cord injury. Class II medical evidence indicates that the majority of thromboembolic events occur in the first 3 months following acute SCI and very few occur thereafter. For these reasons, it is recommended that prophylactic therapy be discontinued after 3 months unless the patient is at high risk for a future VTE event (previous thromboembolic events, obesity, advanced age). It is reasonable to discontinue therapy earlier in patients with retained lower extremity motor function after spinal cord injury, as the incidence of thromboembolic events in these patients is substantially lower than among those patients with motor complete injuries.
Although the guidelines author group concluded that caval filters appeared to be efficacious for the prevention of PE in SCI patients in the 2002 guideline on this topic, more recent medical evidence suggests that prophylactic filters may be more morbid than initially believed. Caval filters still have a role for SCI patients who have suffered thromboembolic events despite anticoagulation, and for SCI patients with contraindications to anticoagulation and/or the use of pneumatic compression devices.
There are several methods available for the diagnosis of DVT. Venography has long been considered the best test, but is invasive, not applicable to all patients, and is associated with intrinsic morbidity. Duplex Doppler ultrasound, impedence plethysmography, venous occlusion plethysmography and the clinical examination have been reported to have sensitivities of approximately 90% and are non-invasive. It is recommended that these noninvasive tests be used for the diagnosis of DVT in SCI patients and that venography to diagnose DVT be reserved for the rare situation when clinical suspicion is high and the results of ultrasound or plethysmography testing are negative.
KEY ISSUES FOR FUTURE INVESTIGATION
Although thromboembolic events in the SCI patient are associated with significant morbidity, no study has demonstrated improved outcomes in SCI patients as a result of surveillance testing for them. A prospective study evaluating 6-month outcomes in patients treated with prophylaxis with or without surveillance ultrasound imaging would be a substantial and potentially cost-saving contribution to the literature.
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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Deep venous thrombosis; Pulmonary embolism; Venous thromboembolism
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