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11. Heterotopic Ossification and Venous Thromboembolism Post Acquired Brain Injury

Robert Teasell MD FRCPC, Shannon Janzen MSc, Daniel McCarthy MD (cand), Caitlin Cassidy MD, Magdalena Mirkowski MSc MScOT OT Reg.(Ont.), Shawn Marshall MSc MD FRCPC, Nora Cullen MSc MD FRCPC

Abbreviations

ABI                         Acquired Brain Injury
CTPA                     Computed Tomography Pulmonary Angiogram
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
SCD                        Sequential Compression Devices
TBI                          Traumatic Brain Injury
V/Q                        Ventilation/Perfusion
VTE                        Venous Thromboembolism

Key Points


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

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

Radiotherapy 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 and functional ability.

Earlier surgical excision may not increase the risk of further heterotopic ossification, and may decrease surgical complications and increase functional outcomes.

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.

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.

Administration of pharmacological thromboembolic prophylaxis within the first 72 hours post ABI may be effective for reducing the risk of developing venous thromboembolism.

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

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 VTE are preventative measures. Information on diagnostic tools is also provided for both complications

11.1 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; Simonsen et al., 2007; Zychowicz, 2013). Risk factors include skeletal trauma, spasticity, diffuse axonal injury, mechanical ventilation, prolonged immobilization, and injury severity (Huang et al., 2018; 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.

11.1.1 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 potentially 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).

There are neurogenic factors contributing to HO, although the mechanisms are not entirely clear yet (Brady et al., 2018; Hurvitz et al., 1992; Moreta & de los Mozos, 2014; 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).

11.1.2 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 deep vein thrombosis (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).

11.1.3 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 for high inter-observer variability and poorly addressing information relevant to cases of neurogenic HO (Della Valle et al., 2002; Mavrogenis et al., 2012; Toom et al., 2005).

11.1.4 Prevention of Heterotopic Ossification

The development of HO in patients with TBI is hard to predict, making preventative treatment challenging. Prophylactic treatment options for HO include range of motion exercises, nonsteroidal anti-inflammatory medications, low-dose radiation, and etidronate disodium (EHDP) (Watanabe & Sant, 2001). Research on the efficacy of these treatments in patients with TBI is limited, and generally focused on secondary prevention after treatment of established HO. Further investigation is needed to develop more effective preventative treatments (Brady et al., 2018).

11.1.4.1 Continuous Passive Range of Motion

Continuous passive motion devices have shown promising results in maintaining range of motion following total knee replacement (Nadler et al., 1993; Salter, 1996). Animal data shows that continuous passive motion does not increase the progression of HO (van Susante et al., 1996). Moreover, there is little human research evidence that HO is worsened by passive range of motion (Linan et al., 2001). Continuous passive range of motion for HO in patients with TBI has only been evaluated in combination with surgical excision, which is discussed later. Further research is needed in the ABI population.

11.1.4.2 Nonsteroidal Anti-Inflammatory Drugs

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 (Fransen & Neal, 2004; Kjaersgaard-Andersen & Schmidt, 1986; Ritter & Sieber, 1985). In patients with spinal cord injuries, preliminary studies of indomethacin or selective Rofecoxib (a selective COX-2 inhibitor) have shown decreased incidence of HO (Banovac et al., 2004; Banovac et al., 2001). 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.

11.1.4.3 Etidronate Disodium

Key Points

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

The use of EHDP, a bisphosphate, in the prophylaxis and treatment of HO is not well studied in the ABI population. 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, 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, 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.

11.1.5 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 has 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 patients with ABI 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.

11.1.5.1 Physiotherapy and Range of Motion Exercises

Key Points

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

At one time, the literature on range of motion therapy post ABI suggested that such experiences actually contributed to the development of HO (Chantraine & Minaire, 1981; Crawford et al., 1986). A shift in thinking practice then occurred 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, although not specific to patients with ABI, careful and judicious use of physiotherapy involving assisted range of motion exercises and gentle stretching are beneficial. 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). Moreta et al. (2014) similarily recommend early joint mobilization, physical therapy and passive range of motion in patients with TBI; however, these recommendations are based on patients with spinal-cord injury.

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). Patients with ABI also 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.

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.

11.1.5.2 Radiotherapy and Extracorporeal Shock Wave Therapy

Key Points

Radiotherapy 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 aim of shockwave and radiotherapy is to disrupt the bone formations through either vibration or radiation (Lee et al., 2016; Reznik et al., 2017a). The goal of radiotherapy 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. Radiotherapy is also used after surgical interventions to decrease the chances of recurrence, which is discussed in section 11.2.5.3. Shock wave/vibration therapy, in contrast, seeks to erode unwanted formations of bone (Reznik et al., 2017a).

Discussion

Recent studies have shown that there are potential alternatives for 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. 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.

11.1.5.3 Surgical Interventions

Key Points

Surgical excision of heterotopic ossification may improve range of motion and functional ability.

Earlier surgical excision may not increase the risk of further heterotopic ossification, and may decrease surgical complications and increase functional outcomes.

Surgical excision of the heterotopic bone is the treatment of choice for those in whom HO has generated marked functional impairment or ulcers in the skin due to deformity (Brady et al., 2018; Moreta & de los Mozos, 2014; 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, earlier surgical intervention has shown decreased osteopenia and ankylosis, without increased rates of recurrence (Almangour et al., 2016; Genet et al., 2012; 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.

Discussion

Fourteen studies examined the effects of surgical excision of HO: two studies focused on the shoulder (Fuller et al., 2013; Pansard et al., 2013) three on the elbow (de Palma et al., 2002; Ippolito et al., 1999b; Lazarus et al., 1999), two on the hips (Genet et al., 2009; Ippolito et al., 1999a), three for the knees (Charnley et al., 1996; Fuller et al., 2005; Ippolito et al., 1999c) and three examined a combination of joints (Kolessar et al., 1996; Melamed et al., 2002; Moore, 1993).

Overall, the surgical excision of HO resulted in improved range of motion. One study did note a decrease in range of motion for a small portion of participants (Ippolito et al., 1999a). Improvements in activities of daily living and ambulation were also found (Fuller et al., 2013; Fuller et al., 2005; Ippolito et al., 1999a, 1999b; Melamed et al., 2002). A 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 with improved outcomes. It is also 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). Additionally, Genet et al. (2009) found progression of HO to ankylosis of the hip lead to non-use and osteopenia, which increased perioperative complications. Furthermore, several reviews have indicated that early surgical excision improves functional outcomes (Almangour et al., 2016; Brady et al., 2018; Genet et al., 2011).

In many studies, the recurrence of HO was evaluated months following the initial operation, with rates ranging from 0 to 27% (Fuller et al., 2013; Fuller et al., 2005; Genet et al., 2012; Ippolito et al., 1999b; Ippolito et al., 1999c; Kolessar et al., 1996; Moore, 1993; Pansard et al., 2013). Variability of study protocol makes comparisons of recurrence difficult; between each study there are differences in follow-up schedules, post-operative management, which joint is examined, and prophylactic treatment for recurrence. The prophylactic treatments used include indomethacin (Charnley et al., 1996; de Palma et al., 2002; Ippolito et al., 1999a; Lazarus et al., 1999), etidronate disodium (Fuller et al., 2005; Moore, 1993), radiotherapy (Fuller et al., 2013; Melamed et al., 2002), a combination (Genet et al., 2012; Kolessar et al., 1996), or physiotherapy alone (Genet et al., 2009; Pansard et al., 2013). Furthermore, 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 examining recurrence of HO after surgical excision in patients with TBI by Almangour et al. (2016) identified a similar problem; estimations of recurrence rates varied widely (5.6% – 58%) based on radiographic, clinical or surgical definitions of recurrence. Importantly however, Almangour et al. (2016) found no relationship between timing of surgery, preoperative extent of HO, or severity of neurological sequelae and incidence of recurrence. This was consistent with the findings of Genet et al. (2012) and another systematic review by Chalidis et al. (2007), where there was no relationship between timing of surgery and recurrence. Therefore, surgical excision was recommended as soon as comorbid factors are controlled (Almangour et al., 2016). Another 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).

Only one study formally evaluated the effectiveness of physical rehabilitation therapy after surgery. The study conducted by Lazarus et al. (1999) found that patients who had continuous passive motion exercises post operatively made significantly greater gains those individuals who did not (57.9° versus 24.1°, p=0.04).

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 early surgical excision does not increase the recurrence risk of heterotopic ossification compared to delayed surgical excision.

11.2 Venous Thromboembolism

Venous thromboembolism (VTE) is a blood clot that forms within a vein. The most common place for a blood clot to form is a deep vein, which is called a deep venous thrombosis or DVT. If the clot breaks off and travels to the lungs, causing partial or full occlusion, it is called a pulmonary embolism (PE) (Office of the Surgeon et al., 2008). Together, DVT and PE are referred to as VTE. 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 VTE. 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 VTE to an ABI population.

11.2.1 Incidence of Venous Thromboembolism 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). 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 (INESSS-ONF, 2017; 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).

11.2.2 Risk Factors for DVT Post Head Injury

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 VTE 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.              

11.2.3 Clinical Presentation of Deep Vein Thrombosis and Pulmonary Embolism

A study found that up to 91% of thrombi form below the iliac level (De Maeseneer et al., 2016). 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.

11.2.4 Diagnostic Testing for Deep Vein Thrombosis

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 in patients with low clinical suspicion of DVT (Carlile et al., 2006).

11.2.4.1 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.

11.2.4.2 Venography

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

11.2.4.3 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.

11.2.5 Diagnostic Testing for Pulmonary Embolism

The diagnostic work-up for a suspected PE is a step-wise decision algorithm consisting of clinical likelihood and D-dimer testing (Di Nisio et al., 2016; Moore et al., 2018). Patients with low clinical suspicion of PE have D-dimer testing. If the D-dimer is negative, PE is ruled out in patients with low clinical suspicion of PE; if positive, patients move to imaging for PE. Patients with high clinical suspicion of PE do not have D-dimer testing and move straight to imaging. Patients with ABI are most often considered high-risk for PE. Computed Tomography Pulmonary Angiogram (CTPA) is the preferred imaging modality for diagnosis of PE (Di Nisio et al., 2016; Moore et al., 2018). Ventilation/Perfusion Scanning (V/Q Scan) can be used when CTPA is contraindicated. Combining imaging with pre-test clinical decision rules increases the predictive power in the diagnosis of PE.

11.2.5.1 Ventilation/Perfusion Scanning

Palmowski et al. (2014) reported the sensitivity and specificity of V/Q 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.

Discussion

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). For this reason, in addition to limited availability of V/Q scans, CTPA is the preferred investigation for PE imaging.

11.2.5.2 Computed Tomography Pulmonary Angiogram

CTPA is the preferred imaging modality for diagnosing PE (Di Nisio et al., 2016; Moore et al., 2018). It has become first line at most centers because it is fast, highly sensitive and specific, and can detect other causes of chest pain such as pneumonia, musculoskeletal injuries or pericardial abnormalities (Di Nisio et al., 2016). Combined with clinical probability rules there is a very high positive predictive value (Gottschalk et al., 2002; Stein et al., 2006). CTPA carries risks associated with radiation exposure, bleeding, adverse reaction to contrast medium, and is contraindicated in renal insufficiency. V/Q scan is used for investigating potential PE when CTPA is contraindicated (Di Nisio et al., 2016).

11.2.6 Prevention of Venous Thromboembolism Post ABI

Several interventions have been examined for the prevention of DVT after an ABI, including mechanical therapy, pharmaceuticals, or a combination of both. In a systematic review, Hachem et al. (2018) found rates of VTE in patients with severe TBI not receiving anticoagulation prophylaxis were near 30%, compared to 5-10% of patients with prophylaxis. However, there is no agreement on the administration of these medications in terms of timing, dose, and/or which anticoagulation medication.

11.2.6.1 Non-Pharmacological Prophylaxis

Key Points

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.

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.

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 patients with severe brain injury. 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.

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). However, Minshall et al. (2011) found that mortality was higher in the group of patients receiving sequential compression devices alone compared to LMWH or UFH.

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. 

There is conflicting evidence regarding the effectiveness of intermittent pneumatic compression devices compared to low-molecular-weight heparin or unfractionated heparin for the prophylaxis of DVT and PE.

11.2.6.2 Pharmacological Prophylaxis

Key Points

Administration of pharmacological thromboembolic prophylaxis within the first 72 hours post ABI may be effective for reducing the risk of developing venous thromboembolism.

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

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 dose range for prophylaxis and treatment of thromboembolism are the same (Hirsh et al., 1992; Hyers et al., 1992; Landefeld & Goldman, 1989).

In a multicenter observational study of DVT prophylaxis with a mixed TBI population sample of 932 patients treated with anticoagulation drugs, 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 Institut national d’excellence en santé et en services sociaux (INESSS) and Ontario Neurotrauma Foundation clinical practice guidelines for the rehabilitation of moderate to severe TBI recommend initiating thromboprophylaxis as soon as medically appropriate (level B evidence), and physical methods of thromboprophylaxis (ie. compression stockings) should be used when pharmacological prophylaxis is delayed or contraindicated (level B evidence)(INESSS-ONF, 2017). 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). A systematic review on anticoagulation in patients with severe TBI found 30% rate of VTE among patients not receiving anticoagulation compared to 5-10% in patients receiving anticoagulation therapy (Hachem et al., 2018).

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).

Differences in medications used for pharmacological thromboprophylaxis of patients with ABI is another important consideration. 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). LMWH, which is injected subcutaneously, has gained popularity due to the ease of administration and dosage adjustment. Of note, low-molecular weight variants of unfractionated heparin are more expensive but the advantages are such that they have become the standard of care. 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). These results are consistent with Byrne et al. (2017) matched analysis in patients with isolated severe TBI, where patients who received LMWH had an adjusted odds ratio of 0.49 (95% CI=0.29-0.82) of developing a PE compared to patients who were treated with unfractionated heparin. The INESSS and Ontario Neurotrauma Foundation clinical practice guidelines for the rehabilitation of moderate to severe TBI recommends LMWH over unfractionated heparin after TBI (level C evidence), although these guidelines are mostly based on evidence in general trauma patients, and not TBI specifically (INESSS-ONF, 2017).

Discussion

Results indicate that early anticoagulation 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 Meyer et al. (2016) and Hachem et al. (2018), which found no increased risk of ICH worsening, but found no benefit regarding VTE incidence.

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) concluded that individuals who begin pharmacological thromboprophylaxis within 72 hours of injury have half the risk of VTE without significantly increased 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, indicative of a more severe brain injury, no significant differences were reported for rate of DVT and PE when comparing those who received enoxaparin prophylaxis 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.

A systematic review of twelve studies reported that overall evidence supported the use of enoxaparin for reduction of DVT and unfractionated heparin for decreased mortality rates compared to no chemoprophylaxis (Chelladurai et al., 2013). Furthermore, a retrospective study of 20 417 patients with isolated TBI reported less likelihood of VTE with LMWH compared to unfractionated heparin (Benjamin et al., 2017).

Conclusions

There is level 3 evidence that prophylactic anticoagulation is 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 enoxaparin 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 enoxaparin or heparin post ABI does not increase the risk of intracranial bleeding compared to no treatment.

11.3 Conclusions

Neurogenic HO is common but the actual etiology is not completely understood and there is a need to research effective prophylactic interventions. The most effective intervention for the treatment of HO overall is surgical excision. The most well studied intervention for the prevention of VTE is pharmacological thromboprophylaxis. There is moderate evidence that pharmacological prophylaxis with heparin, particularly LMWH helps reduce the risk of developing a VTE post ABI, without increasing the risk of intracranial bleeding in patients with TBI. Compression stockings are not more effective than LMWH. Unfortunately, the evidence in ABI specific populations is limited; the timing, agent and methods of anticoagulation therapy would benefit from more research.

Summary


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 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 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 surgical excision of heterotopic ossification may improve range of motion in ABI populations.

There is level 3 evidence that early surgical excision does not increase the recurrence risk of heterotopic ossification compared to delayed surgical excision.

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 conflicting evidence regarding the effectiveness of intermittent pneumatic compression devices compared to low-molecular-weight heparin or unfractionated heparin for the prophylaxis of DVT and PE.

There is level 3 evidence that prophylactic anticoagulation is 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 enoxaparin 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 enoxaparin or heparin post ABI does not increase the risk of intracranial bleeding compared to no treatment.

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