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11. Heterotopic Ossification and Venous Thromboembolism Post Acquired Brain Injury

Abbreviations

ABI                         Acquired Brain Injury

DVT                       Deep Venous Thrombosis

EHDP                    Etidronate Disodium (ethane-1-hydroxy-1, 1-diphosphonate)

GCS                     Glasgow Coma Scale

HO                          Heterotopic Ossification

LMWH                    Low-Molecular Weight Heparin

PCT                        Prospective Controlled Trial

PE                           Pulmonary Embolism

PIOPED                 Prospective Investigation of Pulmonary Embolism Diagnosis

SCD                        Sequential Compression Devices

TBI                          Traumatic Brain Injury

VTE                        Venous Thromboembolism

Key Points


Forceful joint manipulation may prevent bony ankylosis post ABI and may increase range of motion  in joints affected by heterotopic ossification.

Etidronate Disodium may prevent the development of heterotopic ossification in individuals with ABI.

Radiation therapy and shock wave therapy may be effective for the treatment of pain and/or range of motion associated with heterotopic ossification in ABI populations.

Surgical excision of heterotopic ossification may improve range of motion.

A delay in surgical excision may not increase the risk of further heterotopic ossification recurrence.

Combining surgical excision with etidronate disodium, indomethacin, and/or passive motion therapy may improve range of motion in individuals post-ABI.

Sequential compression devices may not reduce the risk of developing deep vein thrombosis or pulmonary embolism post ABI.

Intermittent compression devices do not aggravate intracranial hemodynamics in patients with severe ABI.

Administration of pharmacological deep vein thrombosis prophylaxis within the first 72 hours post ABI may be effective for reducing the risk of developing deep vein thrombosis.

Enoxaparin is effective for the prevention of Venous Thromboembolism development after elective neurosurgery and has not been found to cause excessive bleeding.

Compression stockings may be more effective at preventing venous thromboembolisms when combined with low-molecular weight heparin post ABI

Intermittent pneumatic compression devices and low molecular weight heparin may have a similar effect in terms of the prevention of deep vein thrombosis post ABI when compared to each other.

Introduction

This module aims to provide information regarding what is currently known about the etiology and treatment of heterotopic ossification (HO) and venous thromboembolism (VTE) following acquired brain injury (ABI). Additionally, it is worth noting that the majority of interventions discussed for HO and DVT are preventative measures, as there is limited evidence regarding available interventions for either complication in the setting of ABI. Information on diagnostic tools is also provided for both complications. The studies included in this module follow the same inclusion criteria as other modules and is outlined in Module 1.

11.2 Heterotopic Ossification (HO)

HO is the formation of pathologic bone within soft tissues, often muscle tissues, where bone formation does not usually occur (Watanabe & Sant, 2001). The incidence of HO in patients with traumatic brain injury (TBI) has been reported to range from 11% to 77% but is clinically relevant in 10-20% (Dizdar et al., 2013; Garland et al., 1980; Rogers, 1988; Sarafis et al., 1999; Sazbon et al., 1981; Zychowicz, 2013). Risk factors include skeletal trauma, spasticity, diffuse axonal injury, mechanical ventilation, prolonged immobilization, and injury severity (Moreta & de los Mozos, 2014). HO is often quite painful and limits joint mobility; the restricted joint range of motion may exacerbate disability and impede progress towards desired rehabilitation goals.

11.2.1 Formation of Heterotopic Ossification Post Head Injury

The pathophysiology of HO is not fully understood. Mesenchymal stem cells are pleuripotent cells that can differentiate into cells capable of generating cartilage, bone, muscle, tendons, ligaments, or fat (Pape et al., 2004). It is thought that they play a pivotal role in the development of HO (Williams et al., 1999). HO development begins with the formation of osteoid periarticularly and intramuscularly, and progresses to full calcification within a matter of weeks (Pape et al., 2001). Over the next few months, the calcified osteoid remodels into well-organized trabecular bone at which point it is considered to have matured (Pape et al., 2001). Several months after the initial trauma, patients with HO begin to experience restricted range of motion, pain, and ankylosis (Banovac & Gonzalez, 1997; Garland et al., 1980). The bony lesion has been found to have a high metabolic rate, with a rate of bone formation more than three times greater than that of normal bone, and an osteoclastic density of more than twice the density found in normal bone (Puzas et al., 1987).

It is believed that there is likely a neurogenic factor contributing to HO, although this mechanism is not yet understood (“Collaborative overview of randomised trials of antiplatelet therapy – III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients,” 1994; Hurvitz et al., 1992; Pape et al., 2001; Pape et al., 2004). It has also been noted that circulating factors promoting HO may be present in patients with head injuries (Pape et al., 2004). Many studies have shown enhanced osteogenesis in patients sustaining TBI (Trentz et al., 2005). The presence of certain hormonal factors early post injury influences the stimulation of osteoprogenitors within skeletal muscles (Ivanhoe et al., 2012). Further, tissue hypoxia, sympathetic changes, immobilization, remobilization, and spasticity are additional risk factors (Ivanhoe et al., 2012). Accelerated fracture healing and HO are well documented phenomena in these patients (Bidner et al., 1990; Keret et al., 1990).

11.2.2 Clinical Presentation of Heterotopic Ossification

Among individuals with TBI, the most common sites of HO are the soft tissues around the hip, elbow, shoulder, and knee (Garland, 1991; Garland et al., 1980; van Kampen et al., 2011; Vanden Bossche & Vanderstraeten, 2005). The hip is the most frequent site of ossification (Dizdar et al., 2013; Vanden Bossche & Vanderstraeten, 2005), with total ankylosis of the joint occurring in 5-16% of affected hips (Stover et al., 1991). HO of the shoulder has been found to affect 5% of individuals with a brain injury (Cipriano et al., 2009), while the knee is a less common site for HO following a head injury (Sarafis et al., 1999). When HO is present in the knee, it is usually seen medially (Hosalkar et al., 2013). The distribution of HO around the elbow occurs most commonly either anteriorly in the flexor muscles or posteriorly in the extensors (Sarafis et al., 1999). Of the joints affected by HO after head injury, ankylosis is most likely to occur in the posterior elbow (Garland et al., 1980).

The onset of HO has been reported to vary between two and three weeks post injury (Watanabe & Sant, 2001). More recently, clinical signs and symptoms have been reported to develop 3-12 weeks post injury (Vanden Bossche & Vanderstraeten, 2005; Zychowicz, 2013). Pape and colleagues (2004) noted that clinical examination in the setting of HO may reveal a swollen, warm, painful joint which is often associated with decreased range of motion. The earliest sign is typically a loss of range of motion in the involved joint (Watanabe & Sant, 2001). Other indicators include erythema, palpation of a periarticular mass, and fever (Varghese, 1992). Because of the association with fever, it is sometimes difficult to differentiate HO from infection (Citta-Pietrolungo et al., 1992; Garland, 1991; Garland et al., 1980). Moreover, the clinical picture may be confused with DVT, local trauma, or fracture (Buschbacher, 1992; Jensen et al., 1987). HO will then progress from these initial symptoms into a mass with stiffness and induration (Zychowicz, 2013). Potential complications of HO include compression of blood vessels and nerves, breakdown of associated tissue, restricted motion, and loss of function (Zychowicz, 2013).

11.2.3 Diagnostic Testing for Heterotopic Ossification

During the initial presentation, plain radiographs may be negative and will usually remain normal until ossification begins at approximately 4-6 weeks post injury. Serum levels of alkaline phosphatase, a glycoprotein in the plasma membrane of osteoblasts, and the erythrocyte sedimentation rate may become elevated early on but are non-specific. The triple phase technicium-99 bone scan remains the diagnostic gold standard. The test is positive if there is increased uptake during the first and second phases of the study. It typically becomes positive when clinical features appear (i.e., before an x-ray would be positive).

In the HO literature there are several classification systems, with the Brooker classification system being one of the most widely used. The Brooker Classification system is typically used to classify ectopic-bone formation after total hip replacement. The system is based on anteroposterior radiographs of the pelvis and the categorization of the progression of HO into classes (Brooker et al., 1973). Brooker et al. (1973) define Class I as islands of bone within soft tissues about the hip; Class II as bone spurs from the pelvis or proximal end of the femur with at least 1cm between opposing bone surfaces; Class III as bone spurs from pelvis or proximal end of the femur, reducing space between opposing bone surfaces to less than 1cm; and Class IV as apparent bony ankylosis of hip. This classification system has been criticized and consequently has been modified (Della Valle et al., 2002; Mavrogenis et al., 2012; Toom et al., 2005; Wright et al., 1994).

11.2.4 Prevention of Heterotopic Ossification

Prophylactic treatment options for HO include range of motion exercises, nonsteroidal anti-inflammatory medications, low-dose radiation, warfarin, and etidronate disodium (EHDP) (Watanabe & Sant, 2001). As surgical excision is the most effective intervention once HO has already occurred, the majority of the literature focuses on preventative treatment.

11.2.4.1 Non-Pharmacological Prophylaxis

Key Points

Forceful joint manipulation may prevent bony ankylosis post ABI and may increase range of motion  in joints affected by heterotopic ossification.

Previous literature on range of motion therapy post ABI suggested that this actually contributed to the development of HO (Chantraine & Minaire, 1981; Crawford et al., 1986). Other literature demonstrated a shift in thinking and practice towards the utilization of range of motion exercises, and even joint manipulation under anesthesia, to help prevent ankylosis in patients with ABI (Garland, 1991; Garland et al., 1982). Pape et al. (2004) have noted that for HO, careful and judicious use of physiotherapy, involving assisted range of motion exercises and gentle stretching, are beneficial. However, it has been cautioned that care should be taken not to move the joint beyond its pain-free range of movement as this can exacerbate the condition (Evans, 1991; Pape et al., 2004).

Discussion

Research in this area is limited; however, case study examples have shown physiotherapy with assisted range of motion to be beneficial (Ellerin et al., 1999). Garland et al. (1982) conducted a review of patients with TBI who underwent forceful manipulation of joints with pre-existing HO under anesthesia and reported that it was useful in maintaining and increasing range of motion. With 82% of joints having increased range of motion, the authors concluded that forceful manipulation is not only useful in maintaining motion but also aids in the prevention of bony ankylosis and did not appear to exacerbate the ossification process (Garland et al., 1982; Garland & Varpetian, 2003). Garland and Varpetian (2003) also noted that patients with ABI frequently suffer from spasticity, intolerance to pain, and voluntary muscle guarding. As a result, anesthesia may be needed to help differentiate between spasticity and ankylosis and to allow for sufficient muscle relaxation to perform the joint manipulation (Garland & Varpetian, 2003).

Conclusions

There is level 4 evidence that forceful manipulation under general anesthesia may increase range of motion and prevent bony ankylosis in patients with heterotopic ossification following brain injury.

11.2.4.2 Pharmacological Prophylaxis

Key Points

Etidronate Disodium may prevent the development of heterotopic ossification in individuals with ABI.

The evidence for nonsteroidal anti-inflammatory medications as prophylactic treatment for HO stems mostly from the use of indomethacin or ibuprofen in patients following total hip arthroplasty (Kjaersgaard-Andersen & Schmidt, 1986; Ritter & Sieber, 1985). Although it has been reported that the prophylactic use of these medications significantly decreases HO formation following total hip arthroplasty, it is not known if they have the same effect in the ABI population.

The use of EHDP, a bisphosphate, in the prophylaxis and treatment of HO is controversial (Watanabe & Sant, 2001). EHDP works by preventing the aggregation, growth, and mineralization of calcium hydroxyapatite crystals which are essential for bone formation. EHDP may potentially delay fracture healing, as long-term use has been associated with osteomalacia.

Discussion

Although EHDP has been shown to be effective in reducing HO in other populations, such as spinal cord injury, its effectiveness among individuals with brain injury is less well studied. In an ABI population, Spielman et al. (1983) found that patients treated with EHDP showed a significantly lower incidence of HO than the control group. However, due to the small sample size of the study and the research design, additional research assessing the benefit of EHDP for the prevention of HO following brain injury is needed.

Conclusions

There is level 2 evidence that etidronate disodium may reduce the incidence of heterotopic ossification compared to no etidronate disodium in patients with severe head injury.

11.2.5 Treatment of Heterotopic Ossification

The vast majority of HO interventions include the surgical excision of the affected area. As HO can be challenging to initially diagnose and have high recurrence rates (Almangour et al., 2016), it is important to determine which interventions are successful for the direct treatment of HO. Unlike patients with spinal cord injury, the cognitive and functional status of ABI patients is not a predictor of recurrence (Almangour et al., 2016); therefore, it is more difficult to infer which patients are most likely to re-develop HO, reinforcing the need for effective interventions.

11.2.5.1 Non-Pharmacological Interventions

Key Points

Radiation therapy and shock wave therapy may be effective for the treatment of pain and/or range of motion associated with heterotopic ossification in ABI populations.

Recently, there has been a focus on non-pharmacological, non-surgical interventions for the treatment of HO in the literature. The majority of non-surgical treatments for HO aim to disrupt the bone formations through either radiation or vibration (Lee et al., 2016; Reznik et al., 2017a). The goal of radiation therapy is to disrupt mesenchymal stem cell differentiation into osteoblasts during the early phases of HO (Balboni et al., 2006); by doing so, additional bone formation on a specific site should be arrested. Shock wave/vibration therapy, in contrast, seeks to erode unwanted formations of bone (Reznik et al., 2017a). Regardless of the mechanism of action, the overall goal of non-pharmacological interventions for the treatment of HO is to provide a less invasive alternative to surgical excision.

Discussion

Recent studies have shown that there are potential alternatives to the treatment of HO other than surgery, which is invasive and can be inefficient in terms of recurrence rates (Lee et al., 2016). A study by Resnik et al. (2017a) demonstrated that extracorporeal shock wave therapy was successful in reducing pain associated with HO. Additionally, patients experienced a significant improvement in the flexion range of motion of affected knees, however, no significant effects were seen on knee extension or hip range of motions (Reznik et al., 2017b). A study examining the effects of radiation therapy on HO also suggested positive results in terms of reduced pain and blood plasma levels of HO markers (Lee et al., 2016). Furthermore, results demonstrated immediate beneficial effects of radiation therapy on range of motion, in addition to the cessation of HO formation post treatment.

Conclusions

There is level 4 evidence that radiation therapy may prevent further formation of heterotopic ossification in ABI populations.

There is level 4 evidence that radiation therapy may improve range of motion in joints affected by heterotopic ossification in ABI populations.

There is level 4 evidence that extracorporeal shock wave therapy may reduce pain associated with heterotopic ossification in ABI populations.

There is level 4 evidence that forceful manipulation under general anesthesia may increase range of motion and prevent bony ankylosis in patients with heterotopic ossification following brain injury.

11.2.5.2 Surgical Interventions

Surgical excision of the heterotopic bone is suggested as a possible option for those in whom HO has generated marked functional impairment or ulcers in the skin due to deformity (Watanabe & Sant, 2001). A recent systematic review found that as high as 55% of those diagnosed with neurogenic HO required surgery (Almangour et al., 2016). It had been recommended, based on expert opinion, that surgical intervention be considered only 12 to 18 months after HO initiation to ensure that the bone tissue has matured, and to reduce the likelihood of HO recurrence (Garland, 1991; Sazbon et al., 1981); however, trends toward even later surgical intervention are also emerging (Moreta & de los Mozos, 2014). There is some indication that EHDP and nonsteroidal anti-inflammatory medications may be useful in preventing HO recurrence following surgical excision (Watanabe & Sant, 2001). Further studies are needed to corroborate this. Watanabe and Sant (2001) have reported that recurrence of HO following surgical excision usually occurs post-operatively within three months.

Discussion

Four studies examined the effects of surgical excision of HO; three studies focused on the shoulder (Fuller et al., 2013; Genet et al., 2012; Pansard et al., 2013), and two on the hip (Genet et al., 2012; Melamed et al., 2002).

In two studies, the recurrence of HO was evaluated months following the initial operation (Fuller et al., 2013; Fuller et al., 2005; Ippolito et al., 1999a, 1999b; Moore, 1993; Pansard et al., 2013). The majority of the studies did not specify what qualified as recurrence; however a study by Kolessar et al. (1996) found recurrence rates differed based on the classification system utilized (23.8% versus 4.8% using the Brooker classification and the Stover and colleagues classification, respectively). A systematic review conducted by Lee et al. (2013) focused specifically on the surgical excision of HO in the elbow and found improvements in motion, with low levels of recurrence (14.3%). However, complications such as fracture, infection, nerve palsies, wound complications and loss of motion without recurrence were found in 27.5% of cases (Lee et al., 2013).

Overall, the surgical excision of HO resulted in improved range of motion (Fuller et al., 2005; Pansard et al., 2013). Improvements in activities of daily living and ambulation were also found (Fuller et al., 2013; Ippolito et al., 1999a, 1999b; Melamed et al., 2002). It is worth noting that a study by Genet et al. (2012) found no relationship between operative delay and recurrence of HO post-surgery.

Conclusions

There is level 4 evidence that surgical excision of heterotopic ossification may improve range of motion in ABI populations.

There is level 3 evidence that a delay in heterotopic ossification surgical excision does not increase the risk of further heterotopic ossification recurrence in ABI populations compared to immediate surgical intervention.

Surgical excision of heterotopic ossification may improve range of motion.

A delay in surgical excision may not increase the risk of further heterotopic ossification recurrence.

11.2.5.3 Combination Therapies

Often, surgical excision of HO is not sufficient to remediate the loss of functionality caused by HO. Many studies incorporate a combination of interventions with the aim to help patients regain the maximum amount of function possible. Combination therapies most commonly include surgical excision together with passive motion therapy, pharmacological prophylaxis, or both.

Discussion

Many studies examining combination therapies for relief from HO have used passive motion therapy (Fuller et al., 2005; Ippolito et al., 1999b; Lazarus et al., 1999) and have found it to be effective in combination with surgery for improving range of motion. In Fuller et al. (2005), participants completed a rehabilitation program which included a series of passive measures such as stretching and weight bearing. There were no instances of recurrence at 12 weeks, and both extension and flexion range of motion significantly improved. These results are further supported by Ippolito et al. (1999b), who found similar results. Lazarus et al. (1999) specifically examined the additional benefits of adding passive motion therapy to surgical HO excision and found that those who received continuous passive motion therapy had significantly greater improvements in range of motion compared to those that did not receive passive motion therapy. The study conducted by Lazarus et al. (1999) found that patients who had continuous passive motion exercises post operatively made significantly greater gains compared to those individuals who did not (57.9° versus 24.1°, p=0.04).

Several studies combined surgical excision of HO with pharmacological treatment (de Palma et al., 2002; Ippolito et al., 1999a; Moore, 1993). Ippolito et al. (1999a) treated patients with indomethacin and found that at final follow-up (38 months) all patients were pain free and eight of twelve maintained initial gains in range of motion. Fuller et al. (2005) found that, with treatment of etidronate disodium for 2 months after surgery, patients demonstrated significant improvements in ambulation, sitting, and range of motion. Additionally, there were no instances of recurrence. Moore (1993) found similar results with minimal accounts of recurrence and improvement in overall range of motion.

It is worth noting that length of time between injury and surgical resection was found to be a significant predictor of outcome, as longer times were associated with less improvement (Lazarus et al., 1999). Lastly, another correlation of interest was reported by de Palma et al. (2002), who found that range of motion improvement was correlated with level of neurological damage, with lesser damage correlating to improved outcomes.

Conclusions

There is level 4 evidence that surgical excision in combination with passive motion therapy may improve range of motion affected by heterotopic ossification in ABI populations.

There is level 4 evidence that surgical excision in combination with etidronate disodium may improve range of motion affected by heterotopic ossification in ABI populations.

There is level 4 evidence that surgical excision in combination with indomethacin may improve range of motion affected by heterotopic ossification in ABI populations.

Combining surgical excision with etidronate disodium, indomethacin, and/or passive motion therapy may improve range of motion in individuals post-ABI.

11.3 Deep Venous Thrombosis

Venous thromboembolism (VTE) occurs when blood clots form within the venous system. Deep venous thrombosis (DVT) may occur if the clot forms in a deep vein (i.e., in the leg). If the clot breaks off and travels to the lungs, causing partial or full occlusion, it can become a pulmonary embolism (PE) (Office of the Surgeon et al., 2008). VTE remains a common complication in patients who have sustained an ABI (Raslan et al., 2010; Scudday et al., 2011); however the scientific literature specific to ABI is quite limited.  The following section presents ABI specific research regarding the prevention and treatment of DVT. Additional information on clinical presentation and testing practices is presented, however, it should be noted that not all in-text citations refer to research that meets the specific ERABI ABI inclusion criteria (mixed populations, age, mixed ABI severity, etc.) and therefore should be interpreted with caution when considering the application of any tests or indicators of DVT to an ABI population.

11.3.1 Risk Factors for DVT Post Head Injury

In a large sample study consisting of 38,984 individuals with TBI, the incidence of VTE at the time of admission was 1.31% (Olufajo et al., 2016). At one month post injury, the incidence for VTE increased to 1.87% and by one year it was 2.83% (Olufajo et al., 2016). The reported incidence of DVT among patients with TBI ranges from 11% to 54% (Carlile et al., 2010; Cifu et al., 1996; Denson et al., 2007; Geerts et al., 1994). The risk of developing a DVT or PE, in the absence of prophylaxis, is estimated to be approximately 20% post TBI (Haddad & Arabi, 2012) and severity of injury is found to be associated with incidence of VTE in isolated patients with TBI (Van Gent et al., 2014). Decisions on how to treat, and when, are often made on a case by case basis (Tang & Lobel, 2009). Experts recommend beginning pharmacological prophylaxis as early as 48 to 72 hours post injury (Norwood et al., 2001). Unless contraindicated, mechanical thromboprophlaxis and low-molecular weight heparin (LMWH) are recommened in the acute phase of recovery (Haddad & Arabi, 2012).

Cifu et al. (1996) screened 153 patients admitted to a tertiary care brain injury unit within 24 hours of admission for a lower extremity DVT with colour flow duplex Doppler ultrasonography. All patients had received prophylactic intervention with either subcutaneous heparin anticoagulation or intermittent compression devices. The overall incidence of DVTs in those patients with ABI was 13%, while individuals with TBI had an incidence rate of 20%. Most of the DVTs were asymptomatic. Another study found that DVT was present in 31.6% of individuals who sustained a head injury (Ekeh et al., 2010).

Diagram 11.1: Virchow’s Triad

The most recognized risk factors for VTE are venostasis, intimal damage of the vessel wall, and a hypercoagulable state (Virchow’s triad – see Diagram 11.1) (Watanabe & Sant, 2001). Patients with a severe brain injury are commonly immobilized for periods of time as a result of extremity or spine fractures they experienced at the time of their injury (Vergouwen et al., 2008). The incidence of DVT appears to be impacted by length of stay in the intensive care unit and the number of days a patient is on a ventilator. There does not appear to be a correlation between DVT incidence and initial Glasgow Coma Scale (GCS) scores, Injury Severity Scale scores, or the Abbreviated Injury Scale score (Denson et al., 2007). Those at highest risk post injury are those who remain on a ventilator longer than 3 days (Olufajo et al., 2016; Raslan et al., 2010). At 1-year post injury, risk of VTE is greatest for those discharged to extended care facilities compared to home, and for individuals who undergo an operation (Olufajo et al., 2016). Patients involved in trauma that does not specifically involve vessel injury are still at increased risk of thromboembolism, suggesting a trauma-induced hypercoagulable state (Geerts et al., 1994; Geerts et al., 1996). Therefore, persons who have sustained a TBI appear to be at increased risk of developing VTE for multiple reasons.

11.3.2 Clinical Presentation of Deep Vein Thrombosis and Pulmonary Embolism

A recent study found that up to 91% of thrombi form below the iliac level (De Maeseneer et al., 2016), and that the most common symptoms reported when a DVT is present are pain, swelling of the legs, and discoloration of the region (Collins, 2009). The clinical presentation of PE is challenging. Many cases are clinically silent (66%) with only 30% having the clinical features of a DVT (Garcia-Fuster et al., 2014). Asymptomatic PE is discovered in 70% of patients with confirmed clinically symptomatic DVT (Browse, 1974; Corrigan et al., 1974; Hull & Hirsh, 1983). Clinically, PE presents with tachycardia, tachypnea, hemoptysis, pleuritic chest pain and fever. Radiographic findings might include signs of consolidation or pleural effusion (Worku et al., 2014). Massive PE may cause right heart failure, which can progress to cardiovascular collapse, coma, and death.

11.3.3 Diagnostic Testing for Deep Vein Thrombosis and Pulmonary Embolism

A positive diagnosis of DVT can only be made if a venogram is positive or there is a positive venous ultrasound at two or more sites of the proximal veins. The diagnosis of DVT can be ruled out if there is a negative venogram, a negative D-dimer test or a normal venous ultrasound, assuming the venous ultrasound is accompanied by one of the following findings: 1) low clinical suspicion for DVT, 2) negative D-dimer test, or 3) negative serial ultrasound performed one week later. In an email survey, 56% of respondents from acute centers reported the use of venous duplex ultrasonography (VDU) to screen for DVTs post ABI, whereas 13% of rehabilitation hospital responders use D-dimer along with venous duplex ultrasonography for routine screening of DVT post injury (Carlile et al., 2006).

Venous Ultrasound

Venous ultrasound is often used to diagnose a DVT. There are several types of venous ultrasonography. They include compression ultrasound, duplex ultrasound, and color Doppler imaging. Although these types of venous ultrasonography are sometimes used interchangeably, their sensitivities and specificities for detecting acute DVT vary (Zierler, 2004). The sensitivity and specificity of compression ultrasonography for detecting DVTs is 43% and 85%, respectively (Girard et al., 2005). The weighted mean sensitivity and specificity of venous ultrasonography for the diagnosis of symptomatic proximal DVT are 97% and 94%, respectively; the sensitivity falls to 73% for distal DVT (Kearon et al., 1998; Zierler, 2004). Importantly, distal DVTs do not confer the same risk of extension to PE as do proximal DVTs. Typically, if a distal clot is going to extend proximally, this occurs within one week of its development. Consequently, serial ultrasound could be used in symptomatic patients in whom the test is initially negative as the test would become positive with the clot extension.

Venography

Venography is considered a definitive test for DVT but it is an invasive test whereby contrast dye is injected into the leg veins. Diagnosis of DVT is made if an intraluminal-filling defect is noted.

D-dimer Assay

D-dimer assay is a rapid, non-invasive, and inexpensive test. Fibrin is the main component of thrombus formation and fibrin degradation products include D-dimers (Gill & Nahum, 2000). A positive D-dimer test is highly sensitive for the presence of a thrombus but lacks specificity since D-dimers are found in other disease states, including cancer, congestive heart failure, and inflammatory conditions (Raimondi et al., 1993). As a result, D-dimer assays have a high negative predictive value but a poor positive predictive value. To illustrate, Akman et al. (2004) reported that the sensitivity and negative predictive values of the D-dimer test were high, at 95.2% and 96.2% respectively, in a group of 68 rehabilitation patients (stroke, spinal cord injury, TBI, hip arthroplasty). The specificity and positive predictive values were low at 55.3% and 48.7%, respectively. 

Diagnostic Testing for Pulmonary Embolism

Ventilation/Perfusion Scanning

Nuclear ventilation/perfusion scans are often used to investigate possible PE. Palmowski et al. (2014) reported the sensitivity and specificity of ventilation/perfusion scanning as 95.8% and 82.6%, respectively, with false negative rates of 4.2% and false positive rates of 17.3%. Hence, a normal scan virtually excludes a PE (high negative predictive value). Identified perfusion defects are non-specific and only represent true PE in about one-third of cases. The probability that a perfusion defect represents a PE increases with the size, shape, and number of defects as well as the presence of a normal ventilation scan.

The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED Investigators) study demonstrated that a low-probability or normal ventilation-perfusion scan with a low clinical suspicion of PE essentially excludes the diagnosis of PE (negative predictive values of 96% and 98% respectively) (Gill & Nahum, 2000; PIOPED Investigators, 1990). When clinical suspicion is high and the scan indicates a high probability of PE, the positive predictive value is 96% (Gill & Nahum, 2000; PIOPED Investigators, 1990), and these patients should be treated. The majority of ventilation perfusion scans have non-diagnostic results, requiring further testing (PIOPED Investigators, 1990).

Pulmonary Angiography

Pulmonary angiography is the gold standard for diagnosis of PE (Gill & Nahum, 2000). It involves percutaneous catheterization and injection of contrast dye into a pulmonary artery branch (Gill & Nahum, 2000). Pulmonary angiography is most commonly used when ventilation-perfusion scanning is non-diagnostic but clinical suspicion remains high (Tapson et al., 1999). A negative pulmonary angiogram excludes clinically relevant PE (Gill & Nahum, 2000; Tapson et al., 1999). It is expensive and is associated with the risk of significant complications. Relative contraindications include significant bleeding risk, allergy to contrast medium, and renal insufficiency (Gill & Nahum, 2000).

Spiral Computed Tomography (CT) Scan

A spiral computed tomography scan is a non-invasive test which can scan the entire thorax in one breath-hold. The sensitivity of a spinal computed tomography scan in diagnosing PE has been reported to range from 64% to 93%, with a specificity ranging between 89% and 100%. It is most accurate when the embolism is large. It actually visualizes the clot and has the added benefit of investigating other disease states in the differential diagnosis.

11.3.4 Prevention of DVT

Several interventions have been examined for the prevention of DVT after an ABI, including mechanical therapy, pharmaceuticals, or a combination of both. To date, the recommendation for treating those who sustain a DVT post ABI is the administration of preventative medication (Elliott et al., 2006; Scudday et al., 2011). However, there is no agreement on the administration of these medications in terms of timing, dose, and/or which medication.

11.3.4.1 Non-Pharmacological Prophylaxis

Non-pharmacological, mechanical interventions used to prevent the development of DVT post ABI include: the insertion of inferior vena cava filters, thromboembolism deterrent stockings, and intermittent pneumatic compression devices including arteriovenous foot pumps and sequential compression devices (SCDs). These devices operate primarily through two distinct mechanisms of action. The first is mechanical, in which the device increases the velocity of venous return to decrease venous stasis, thus reducing the opportunity for clot formation. The second, and perhaps more important mechanism, involves the systemic activation of the fibrinolytic system which, during compression, leads to the breakdown of fibrin clots associated with thromboembolism (Macatangay et al., 2008). The exception is vena cava filters, which operate by another method of mechanical VTE prevention (Watanabe & Sant, 2001). These filters are inserted into the inferior vena cava to prevent the passage of distal emboli into the lungs. Some reports have demonstrated success rates as high as 96% in the prevention of pulmonary emboli (Greenfield & Michna, 1988). However, the use of vena cava filters carries some associated risks. They can become blocked or dislodged which can increase the risk of an embolism. Some have also reportedly increased risks for repeated DVT compared with patients without such devices (Decousus et al., 1998).

Discussion

Gersin et al. (1994) investigated the effectiveness of SCDs. Of 32 patients admitted to the surgical intensive care unit with severe TBI, a total of eight patients developed DVT or PE following injury, half of whom had received prophylactic SCDs (showing no significant difference between SCDs and no intervention). The effectiveness of prophylactic SCDs in the prevention of post-TBI DVT or PE thus remains questionable.

Davidson et al. (1993) conducted a study to evaluate the possibility that intermittent pneumatic compression could aggravate intracranial hemodynamics in severe brain injury patients. The authors reported that the use of intermittent compression devices to prevent the occurrence of DVT was not associated with any significant changes in intracranial pressure or cerebral perfusion pressure in stable patients in whom intracranial pressure was controlled by conventional measures (Davidson et al., 1993). These findings suggest that there is no contraindication to the use of pneumatic compression for the prevention of DVT in severe acute patients with brain injury who are responsive to conventional intracranial management measures.

Conclusions

There is level 2 evidence that sequential compression devices are not more effective for reducing the risk of developing deep vein thrombosis or pulmonary embolism compared to no sequential compression devices post ABI.

There is level 4 evidence that intermittent compression devices do not cause acute elevations in intracranial pressure in patients with severe ABI.

Sequential compression devices may not reduce the risk of developing deep vein thrombosis or pulmonary embolism post ABI.

Intermittent compression devices do not aggravate intracranial hemodynamics in patients with severe ABI.

11.3.4.2 Pharmacological Prophylaxis

Oral agents have been investigated for their prophylactic potential against DVT. Warfarin (Coumadin), a well-established anticoagulant with a predictable duration of action, is sometimes avoided as a prophylactic alternative for DVT due to its elevated bleeding side effects (Watanabe & Sant, 2001). Albrecht and colleagues (2014) report that warfarin use is associated with lower rates of DVT and PE, but comes at the cost of the risk of increased hemorrhagic bleeding. However, some experts felt the use of warfarin was advisable, especially for high risk patients due to its benefit in treating undetected thrombosis; the therapeutic concentration for prophylaxis and treatment of thromboembolism are the same (Hirsh et al., 1992; Hyers et al., 1992; Landefeld & Goldman, 1989).

In a study of DVT prophylaxis with a mixed population sample of 932 patients, 71% were given LMWH, 23% unfractionated heparin, 1% Coumadin, and 3% were given both LMWH and Low-dose unfractionated heparin, none of which were associated with increased intracranial or systemic hemorrhage (Carlile et al., 2010). The most recent guidelines, for those with ABI, on DVT prophylaxis recommend using LMWH or Low-dose unfractionated heparin in addition to mechanical prophylaxis (Elliott et al., 2006; Reiff et al., 2009). There is also evidence from a meta-analysis that aspirin has positive effects in the reduction of both DVT and PE, by 40% and 60% respectively (“Collaborative overview of randomised trials of antiplatelet therapy – III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients,” 1994). Clinically, there remain concerns that chemical DVT prophylaxis may result in increased intracranial bleeding post ABI.

Overall, there is a lack of persuasive evidence to guide decisions about when to administer anticoagulant prophylaxis in those who sustain traumatic intracranial hemorrhage. Clinicians often make decisions based on their own assessments of the risks and benefits (Scales et al., 2010). To date no national standard of care exists for the administration of the pharmacological prophylaxis treatment of DVT post TBI (Phelan et al., 2012a).

Low Molecular Weight Heparin vs Low Dose Unfractionated Heparin

Subcutaneous heparin in low doses has been reported to be both safe and effective as prophylaxis against DVT development post ABI (Watanabe & Sant, 2001). The route of delivery may also affect the efficacy of anticoagulant prophylaxis (Watanabe & Sant, 2001). For this reason, intravenously delivered heparin may be more effective in the prevention of thromboembolism compared with subcutaneous administration, although this method of delivery might increase the risk of bleeding (Green et al., 1988). Low-molecular weight heparins, which are injected subcutaneously, have gained popularity due to the ease of administration and dosage adjustment. Of note, low-molecular weight variants of unfractionated heparin are significantly more expansive, and thus the risks, benefits, and costs need to be balanced out on an individual basis (Watanabe & Sant, 2001). Carlile et al. (2006) found that 15 of the 16 rehabilitation centers surveyed reported routinely initiating treatment with either LMWH or Low-dose unfractionated heparin. In a study with a mixed trauma population, low-dose unfractionated heparin was compared to enoxaparin (LMWH) for the treatment of DVT (Geerts et al., 1996). Of those receiving low-dose unfractionated heparin, 44% suffered a DVT compared to 31% of patients receiving enoxaparin (p=0.014) (Geerts et al., 1996).

Discussion

Results indicate that early treatment (within the first 72 hours) may reduce the risk of developing DVT post injury (Byrne et al., 2016; Farooqui et al., 2013; Kim et al., 2002; Kim et al., 2014; Norwood et al., 2008; Salottolo et al., 2011; Scudday et al., 2011) without increasing the risk of intracranial hemorrhagic injury (Byrne et al., 2016; Koehler et al., 2011; Scudday et al., 2011) or deterioration on neurological examination (Kim et al., 2002). However, these results are in conflict with one study by Meyer et al. (2016) which similarly found no increased risk of ICH worsening, but found no benefit regarding VTE incidence either.

Patients with ABI who were started on unfractionated heparin within three days of injury onset, compared to those who started after this time period, did not differ significantly in terms of the number of thromboembolic events (Kim et al., 2002; Kim et al., 2014). However, those who received heparin earlier had greater cumulative neuro improvement and lower injury severity scale scores (Kim et al., 2014).

Norwood and colleagues conducted two studies examining the benefits of administering enoxaparin (LMWH) prophylaxis to those who sustain a severe ABI within the first 48 hours post injury (Norwood et al., 2008; Norwood et al., 2002). Results from both studies indicate that administering enoxaparin post ABI reduces the risk of developing DVT and PE, without increasing the risk of bleeding post injury. Scudday et al. (2011) also found that patients who received chemical prophylaxis within 72 hours of injury had a significantly lower incidence of developing VTE post ABI (p<0.019) compared to those not receiving chemical prophylaxis (Kim et al., 2014). Overall, a meta-analysis by Jamjoom and colleagues (2013) conclude that individuals who begin pharmacological thromboprophylaxis within 72 hours of injury have half the risk of VTE without significant risk of intracranial hemorrhage progression, compared to those who start prophylaxis more than 72 hours after their injuries.

On the contrary, a few studies have demonstrated that these medications may not be beneficial or superior treatments. In one study with individuals who underwent a craniotomy post ABI, no significant differences were reported for rate of DVT and PE when comparing those who received enoxaparin prophylaxis compared to those who did not (Daley et al., 2015). Further, Kwiatt et al. (2012) reported that patients receiving LMWH were at higher risk for hemorrhage progression and the risk of using LMWH may exceed its benefit. Similarly for heparin, Lin et al. (2013) did not find a reduction in DVT or PE once individuals with a severe TBI were administered a heparin prophylaxis protocol. Another study has demonstrated that heparin may not be as effective as other anticoagulant treatments (Dengler et al., 2016).

In conclusion, a systematic review of twelve studies reports that overall evidence supports the use of enoxaparin for reduction of DVT and UFH for decreased mortality rates compared to no chemoprophylaxis (Chelladurai et al., 2013).

Conclusions

There is level 1b evidence that enoxaparin is no more effective than placebo in reducing the risk of developing deep vein thrombosis in patients post-ABI.

There is level 2 evidence that the administration of low-molecular weight heparin within the first 72 hours post ABI reduces the risk of developing deep vein thrombosis and pulmonary embolism post injury compared to unfractionated heparin.

There is level 4 evidence that administering low molecular weight heparin (enoxaparin) or heparin post ABI does not increase the risk of intracranial bleeding compared to no treatment.

Administration of pharmacological deep vein thrombosis prophylaxis within the first 72 hours post ABI may be effective for reducing the risk of developing deep vein thrombosis.

Enoxaparin is effective for the prevention of Venous Thromboembolism development after elective neurosurgery and has not been found to cause excessive bleeding.

11.3.4.3 Combination or Comparative Therapies

Compression stockings and pneumatic compression devices are among the most common non-pharmacological strategies used for the prevention of DVT in trauma patients (Watanabe & Sant, 2001). Such mechanical methods may be more advisable than the use of anticoagulants due to the increased risk of bleeding in patients with multiple fractures and injuries (Watanabe & Sant, 2001). These mechanical strategies have demonstrated positive results in the prophylaxis of DVT in neurosurgical patients (Turpie et al., 1989). There is some evidence that the effectiveness of these mechanical devices in the prevention of DVT could also be increased in combination with carefully selected low molecular weight anticoagulants that carry low bleeding risks (Agnelli et al., 1998).

Discussion

In an RCT conducted by Agnelli et al. (1998), patients due to undergo elective neurosurgery within 24 hours were placed on LMWH or a placebo, and were also fitted with compression stockings. DVTs were more common in the placebo group than the intervention group (p<0.004). The combination of both the compression stockings and LMWH appeared to be more beneficial than the compression stockings alone (Agnelli et al., 1998). Agnelli et al. (1998) also reported an additive reduction in thromboembolism, without a significant increase in bleeding risks, in patients with brain injury treated with both enoxaparin and compression stockings compared with patients treated with mechanical compression alone. These conclusions have been supported by more recent literature (Praeger et al., 2012). However, when intermittent pneumatic compression devices were compared to prophylactic LMWH for the prevention of VTE, no significant differences in the development of PEs or DVTs were found between groups (Kurtoglu et al., 2004).

Conclusions

There is level 1b evidence that low-molecular weight heparin combined with compression stockings is more effective than compression stockings alone for the prevention of deep vein thrombosis following elective neurosurgery post ABI, and that the use of low-molecular weight heparin in this setting does not cause excessive bleeding.

There is level 2 evidence that intermittent pneumatic compression devices alone are not more effective compared to low molecular weight heparin for the prevention of deep vein thrombosis post ABI.

Compression stockings may be more effective at preventing venous thromboembolisms when combined with low-molecular weight heparin post ABI

Intermittent pneumatic compression devices and low molecular weight heparin may have a similar effect in terms of the prevention of deep vein thrombosis post ABI when compared to each other.

11.4 Conclusions

When it comes to interventions which are used for the treatment HO and the prevention of DVT, combination therapies appear to have the best results. The evidence also tends to favour prophylactic treatments for both conditions. The most effective intervention for the treatment of HO overall is surgical excision. Unfortunately, research has not been able to delineate the etiology underlying neurogenic HO and as a result there has been a recent focus on prophylactic interventions. With regards to DVT, anticoagulation therapy, which reduces the risk of suffering a DVT without increasing the risk of intracranial bleeding, is the most well studied intervention. LMWH used prophylactically appears to be effective in preventing DVTs without causing increased risk of intracranial bleeding. Unfortunately, due to the limited amount of research available that is directly related to the development of DVTs post ABI, the decision to begin pharmacological prophylaxis post ABI remains a subjective one (Norwood et al., 2008).

Summary


There is level 4 evidence that forceful manipulation under general anesthesia may increase range of motion and prevent bony ankylosis in patients with heterotopic ossification following brain injury.

There is level 2 evidence that etidronate disodium may reduce the incidence of heterotopic ossification compared to no etidronate disodium in patients with severe head injury.

There is level 4 evidence that radiation therapy may prevent further formation of heterotopic ossification in ABI populations.

There is level 4 evidence that radiation therapy may improve range of motion in joints affected by heterotopic ossification in ABI populations.

There is level 4 evidence that extracorporeal shock wave therapy may reduce pain associated with heterotopic ossification in ABI populations.

There is level 4 evidence that forceful manipulation under general anesthesia may increase range of motion and prevent bony ankylosis in patients with heterotopic ossification following brain injury.

There is level 4 evidence that surgical excision of heterotopic ossification may improve range of motion in ABI populations.

There is level 3 evidence that a delay in heterotopic ossification surgical excision does not increase the risk of further heterotopic ossification recurrence in ABI populations compared to immediate surgical intervention.

There is level 4 evidence that surgical excision in combination with passive motion therapy may improve range of motion affected by heterotopic ossification in ABI populations.

There is level 4 evidence that surgical excision in combination with etidronate disodium may improve range of motion affected by heterotopic ossification in ABI populations.

There is level 4 evidence that surgical excision in combination with indomethacin may improve range of motion affected by heterotopic ossification in ABI populations.

There is level 2 evidence that sequential compression devices are not more effective for reducing the risk of developing deep vein thrombosis or pulmonary embolism compared to no sequential compression devices post ABI.

There is level 4 evidence that intermittent compression devices do not cause acute elevations in intracranial pressure in patients with severe ABI.

There is level 1b evidence that enoxaparin is no more effective than placebo in reducing the risk of developing deep vein thrombosis in patients post-ABI.

There is level 2 evidence that the administration of low-molecular weight heparin within the first 72 hours post ABI reduces the risk of developing deep vein thrombosis and pulmonary embolism post injury compared to unfractionated heparin.

There is level 4 evidence that administering low molecular weight heparin (enoxaparin) or heparin post ABI does not increase the risk of intracranial bleeding compared to no treatment.

There is level 4 evidence that the use of chemoprophylaxis 24 hours after stable head computed tomography scan decreases the rate of deep vein thrombosis formation post ABI.

There is level 1b evidence that low-molecular weight heparin combined with compression stockings is more effective than compression stockings alone for the prevention of deep vein thrombosis following elective neurosurgery post ABI, and that the use of low-molecular weight heparin in this setting does not cause excessive bleeding.

There is level 2 evidence that intermittent pneumatic compression devices alone are not more effective compared to low molecular weight heparin for the prevention of deep vein thrombosis post ABI.

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