Management of Venous Thromboembolic Disease in the Chronically Critically Ill Patient

PROLONGED CRITICAL ILLNESS MANAGEMENT OF LONG-TERM A'CUTE CARE

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MANAGEMENT OF VENOUS THROMBOEMBOLIC DISEASE IN THE CHRONICALLY CRITICALLY ILL PATIENT Maged A. Tanios, MD, Amy R. Simon, MD, and Paul M. Hassoun, MD

Venous thromboembolism (VTE) is a spectrum of diseases that can be classified into two categories-deep venous thrombosis (DVT) and pulmonary embolism (PE). The prevalence of VTE is estimated to be 600,000 cases per year, and the mortality rate is 50,000 to 100,000 cases occurring secondary to PE and accounting for 5% to 10% of all hospital deaths in the United state^.^ Although better diagnostic tools have improved the knowledge of the natural history and clinical manifestations of VTE, more than 50% of all cases remain undiagn~sed.~ This occurrence is most likely because of the nonspecificity of signs and symptoms of this disease and the fact that both DVT and PE commonly are unsuspected on clinical grounds and only can be diagnosed with objective testing.lol In addition, despite many studies that demonstrate the efficacy of preventing DVT and, subsequently, PE, many physicians do not incorporate prophylactic therapy into their daily practice.6 The specific problems of diagnosis and management of W E in the ventilated patient in the post acute phase of a severe illness are compounded by several additional factors. Comorbid events contributing to a patient's respiratory symptoms or failure (e.g., exacerbation of chronic obstructive lung disease,

pneumonia, or congestive heart failure) frequently can mask the manifestations of VTE. In addition, the nonspecificity of symptoms (e.g./ chest pain or dyspnea) and signs (e.g./ tachycardia) of a patient on assisted ventilation further contributes to delaying the diagnostic workup for DVT or PE. Finally, the possibility of poor communication between an ill, ventilated patient and the nursing, respiratory, and medical staff caring for this patient can be an additional source of diagnostic confusion. Aside from potential delay in initiating the diagnostic workup for these patients, testing for VTE may be less specific in this context (e.g., perfusion/ventilation scanning in a patient with significant underlying lung disease or pulmonary infiltrates) or technically difficult because of the patient's overall clinical condition. Furthermore, preventive therapy in these patients can be problematic if, for example, there is associated blood dyscrasia or a condition (e.g., gastrointestinal bleed) that prevents anticoagulation. For all of the reasons just mentioned, diagnosis and management of VTE can be challenging particularly in the chronically critically ill patient compared with the patient encountered in an ambulatory setting.

From the Department of Medicine, Division of Pulmonary and Critical Care, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts

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This article reviews the general approach to the diagnosis, management, and prevention of VTE, with a focus on the post acute, mechanically ventilated patient. Because of the paucity or absence of specific information derived from clinical trials and related to DVT and PE in this group, recommendations reflect the authors’ personal experience and bias, which are derived from working in settings dedicated to treatment of these patients. In discussing the various methods used for the diagnosis of VTE in this patient population, several factors are taken into consideration, including the patient’s clinical condition and the availability, feasibility, and cost of a specific test. RISK FACTORS FOR VENOUS THROMBOEMBOLISM

Unusual in the general population, VTE is mostly encountered in hospitalized patients or ambulatory patients with an underlying illness. Approximately 150 years ago, Virchow identified three factors that contribute to thrombus formation: (1) decreased blood flow, (2) vascular injury, and (3) a hypercoaguable state. In one study of more than 1200 patients with VTE, at least one risk factor was present in 96% of the patients? The risk factors for VTE can be inherited or acquired, and combination of these factors now is thought to contribute to the propensity for VTE in certain patients.13,22 Coexistence of hyperhomocysteinemia and factor V Leiden, for instance, sharply increases the risk for VTE.87 As shown in Table 1, the acquired risk factors most often found to lead to VTE include age greater than 40 years, obesity, malignancy, Table 1. RISK FACTORS FOR VENOUS THROMBOEMBOLISM

*

Inherited

Acquired

Resistance to activated protein C (factor V Leiden) Protein C deficiency Protein S deficiency Antithrombin 111 deficiency Lupus anticoagulant Dysfibrinogenemias Abnormalities of fibrinolysis Prothrombin gene mutation Hyperhomocysteinemia

Prior venous thromboembolism Prolonged immobilization Pregnancy Obesity Major surgery Age over 40 years Malignancy Trauma Myocardial infarction Congestive heart failure Lower extremity fracture Estrogen therapy Hyperhomocysteinemia

*

bed rest for greater than 5 days, major surgery, congestive heart failure, and prior VTE.6 One or more of these conditions is present universally in the post acute period of a severe medical or surgical illness. Disorders that are inherited or acquired include protein C and S, antithrombin, and plasminogen deficiencies. These thrombophilias are known to lead to an increased risk for arterial or venous thrombosis.8 Several purely inherited deficiencies that contribute to increased thrombosis have been identified. The presence of factor V Leiden, or resistance to activated protein C, is caused by a transition (guanine to adenine) at nucleotide 1691 (G1691A) in exon 10 of the factor V gene. This genetic defect results in the substitution of a single amino acid in the coagulation factor V protein, making factor Va (an activated coagulant factor) resistant to proteolysis by activated protein C.I3 In one report, the prevalence of this genetic mutation was l6%, making it the most common inherited disorder associated with VTE. The risk for recurrent thromboembolic disease was close to 40% in heterozygous carriers of this genetic abnormality, compared with 18% among patients without the mutation.91Two additional inherited risk factors for VTE were described recently. A transition of guanine to adenosine at position 20210 of the 3’-UT region of the prothrombin gene leads to elevated serum prothrombin levels80and an increased risk for venous thrombosis in heterozygous carriers.12 The 20210A allele is common in white subpopulations and seems to contribute to the risk for thrombosis in carriers of other genetic risk factors, such as factor V Leiden.12 An abnormality in the metabolism of homocysteine, resulting in increased serum and urine levels of this product, is another recognized independent risk factor for venous thrombosis.12Homocysteine is metabolized to cysteine by transsulfuration using cystathionine-p-synthase and pyridoxine, or resynthesized to methionine in a reaction requiring methylcobalamin (B12). Elevated levels of homocysteine concentration can be a result of a rare autosomal recessive congenital type or nutritional deficiencies, such as depleted folate or B12.Increased homocysteine levels also can be found in association with renal insufficiency or liver disease.59The mechanisms by which homocysteine may cause thrombosis are not understood fully; however, endothelial dysfunction caused by hyperhomocys44, 46 Whether inteinemia has been invoked.23, creased levels of serum homocysteine may

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contribute to the development of W E in the chronically critically ill patient remains to be determined. Clinically silent vitamin B12 deficiency, which is frequent at least in the elderly, may cause increased levels of homocysteine, an alteration that responds favorably to vitamin ~upplementation.~~ Vitamin or folate deficiency and the presence of renal or liver failure therefore potentially may cause hyperhomocysteinemia in the chronically critically ill patient, theoretically increasing the risk for VTE, alone or in combination with other inherited or acquired factors. DIAGNOSIS OF DEEP VENOUS THROMBOSIS

Symptoms and Signs It is well recognized that the diagnosis of DVT cannot be established based on the history and physical findings even in patients who are at high risk for VTE.lo8Patients with lower extremity DVT often lack the classic symptoms and signs of erythema, warmth, pain, swelling, or tenderness. This lack is illustrated in a report in which five clinical studies were compared. The sensitivity of calf pain for acute DVT was found to vary from 66% to 91%, whereas the specificity of this symptom varied from 3% to 87Y0.~For calf

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tenderness, the sensitivity was 56% to 82% and the specificity, 26% to 74%. Sensitivity varied from 13% to 48% and the specificity, from 39% to 84% for Homans' sign.&Presence of calf or leg swelling also showed wide disparity among the studies, with the sensitivity varying from 35% to 97% and the specificity, from 8% to 88%.19 In a patient recovering from an acute and often protracted illness, these symptoms and signs often may be missed, ignored, or attributed to conditions other than VTE. Their presence should at least raise the clinical suspicion of DVT, however, and appropriate tests then should be considered to rule out this diagnosis in this highrisk patient. Although contrast venography (CV) remains the gold standard for the diagnosis of DVT, this test is seldom performed because of the availability of several noninvasive tests such as impedance plethysmography (IPG), duplex ultrasonography, and MR imaging. Aside from MR imaging, these noninvasive tests can be performed at the bedside. These tests have lower sensitivity and specificity compared with CV, however, and their results often are dependent on several factors such as the anatomic location of the clot, whether or not the patient is symptomatic, and the expertise of the operator, and other factors. Although each patient presents a particular challenge, a diagnostic algorithm such as that shown in Figure 1 can help diagnose a suspected DVT.

Figure 1. Suspected deep venous thrombosis (DVT).

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Contrast Venography

Although rarely performed, CV remains the gold standard test for the diagnosis of DVT and it is considered to have a sensitivity and specificity of 100%. It is performed with injection of contrast material in a vein on the dorsal aspect of the foot and visualization of the deep venous system from the calf to the pelvic veins and inferior vena cava. A test is considered positive for acute DVT when a persistent intralumenal filling defect or a sharp cutoff of a deep vein are present on multiple views or projections.82The problems of CV include the invasive nature of the test, the possibility of hypersensitivity and idiosyncratic reactions (bronchospasm, urticaria, angioedema, and hypotension) or the development of phlebitis at the site of injection, and the high cost compared with the more commonly performed noninvasive tests. Limitations of CV include poor venous access, nephrotoxicity, or cardiotoxicity. Relative contraindications to CV include acute renal failure and chronic renal insufficiency (serum creatinine level > 2 mg/dL). These contraindications make CV a rather impractical test for the chronically critically ill patient. In addition, the availability of CV in intermediate and long-term care institutions may be limited. Impedance Plethysmography

The usefulness of impedance plethysmography (IPG) for diagnosis of DVT of the proximal lower extremities has been demonstrated in multiple clinical trials.52,58 Like other noninvasive tests such as compression ultrasonography, IPG can be performed at the bedside; IPG has the advantages of requiring less technical training and being less expensive. Impedance plethysmography evaluates the rate of venous return from the lower extremity using the property of venous blood to conduct an electric current between two electrodes placed on the calf. It is insensitive to nonobstructing thrombi that do not decrease the rate of venous outflow and does not discriminate between thrombotic and nonthrombotic obstruction. Elevated central venous pressure, often encountered in chronically critically ill patients, slows venous outflow and may be a cause of bilateral falsepositive results on IPG. The sensitivity and specificity of IPG for detecting proximal DVT

are operator dependent, and the test requires adhering to validated protocols and equipment.lo2Sensitivity and specificity of IPG have varied between 65% and 97%, and 83% and 98%, respectively, when major prospective trials are considered.2Both the sensitivity and specificity of IPG for DVT are significantly lower in asymptomatic patients, however, at least in patients undergoing hip surgery.*,34 Based predominantly on these data, screening for DVT with IPG is not recommended for asymptomatic patients.101Finally, it should be noted that serial IPG testing over a period of 2 weeks can help detect extension of a calf vein thrombus into a more proximal location.52In light of some of the limitations of IPG, this test is not commonly performed in the authors' institution, and other noninvasive methods are preferred for the diagnosis of DVT. Duplex Ultrasonography

Duplex ultrasonography is a widely available noninvasive technique that combines Doppler venous flow detection and real-time ultrasonography. Like IPG, duplex ultrasonography is a safe, inexpensive, operatordependent technique that can be performed at the bedside. In addition, it can be used to detect upper extremity DVT, which is a significant advantage for a population of patients in whom indwelling catheters in central veins are common. Duplex ultrasonography is not useful for iliac or pelvic DVT and not accurate for chronic DVT; however, duplex ultrasonography is essentially helpful for patients with symptomatic proximal DVT and can help exclude other pathologies such as intramuscular hematomas, Baker's cyst, and absce~ses.'~ The sensitivity of duplex ultrasonography and color-flow Doppler ultrasonography in symptomatic patients varies between 88% and 1007'0.~~'The study can be technically limited in a variety of situations, such as when the patient is obese or has significant peripheral edema, or when accessibility to the extremity is difficult to obtain because of the presence of a cast or other immobilization devices. The value of serial ultrasonography for detection of extension of a calf DVT to a proximal vein (common femoral and popliteal veins) has been validated in a study examining symptomatic ~ u t p a t i e n t s . ~ ~ When repeated compression ultrasonography remained negative at days 1, 2, and 8, the

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incidence of VTE was only 1.5% at 6-month follow-up.47Subsequent studies have confirmed the usefulness of serial compression ultrasonography (repeated between 5 and 7 days) in patients with clinically suspected DVT.14,24 In these studies, incidence of W E over a 6-month period was trivial (< 1%in patients with negative studies and in whom treatment had been withheld). Withholding anticoagulation for patients with clinically suspected DVT but with negative ultrasonography studies at presentation and at 1 week, therefore, seems safe. Whether this recommendation applies to the debilitated patient in the post acute phase of an illness remains to be determined. False-positive results because of a pelvic mass or other perivascular pathology15 probably can be encountered with some degree of frequency in this particular patient population. Similarly, false-negative results may be encountered in patients with calf DVT or asymptomatic patients with proximal DVT.Io7In addition, ultrasonography may have limited value for the diagnosis of recurrent DVT because findings do not return to normal after the initial episode of DVT. Because of the common use of indwelling catheters in chronically ill patients, upper extremity DVT can be encountered in this patient group, with an incidence as high as 47% in symptomatic patients.81 Symptomatic upper extremity DVT appears to be significantly correlated with the presence of an indwelling catheter, thrombophilic states, and a previous leg vein thrombosis.81The diagnosis can be established by ultrasonography, CV, or MR imaging; however, ultrasonography evaluation is limited to the internal jugular, subclavian, axillary, and brachial veins. Although the sensitivity of ultrasonography for symptomatic upper extremity DVT is reasonable, ranging from 78% to 1009'0,'~, 63, 81 it is less than 40% in asymptomatic patients after catheter removal.= In the authors' institution, when a DVT of the upper extremity is suspected in the setting of an indwelling catheter, an ultrasonography is obtained first before considering CV or MR imaging. Magnetic Resonance Imaging

Magnetic resonance imaging is being actively investigated as a noninvasive tool for the diagnosis of DVTz8,9z and PE.67The sensitivity and specificity of MR imaging are

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greater than 90% for acute symptomatic proximal DVT.92Compared with previously discussed noninvasive techniques, MR imaging seems to be superior for the diagnosis of pelvic vein thrombosiszo, 29, 92 and may help discriminate between acute and chronic DVT.28This discrimination is a potentially significant advantage over the ultrasonography technique for patients with recurrent episodes of DVT during a protracted course of an illness. The diagnostic role of MR imaging for calf DVT, upper extremity DVT, and asymptomatic DVT remains to be assessed. In addition to being a noninvasive test, MR imaging does not require the use of intravenous contrast material. It can be contraindicated in chronically ill patients, however, if metallic devices or apparatus, are present (e.g., in orthopedic patients). Other potential restrictions of this test include claustrophobia and massive obesity and the limited availability of scanners at smaller institutions. Magnetic resonance imaging should be considered in symptomatic patients when noninvasive tests, such as ultrasonography or IPG, are inconclusive and the use of contrast material is contraindicated. PULMONARY EMBOLISM

Pulmonary embolism remains a clinical challenge despite advances in noninvasive diagnostic modalities. This disease earned the term the great masquerader because of its various clinical manifestations. The appearance of symptoms might alert the clinician to the possibility of PE in a patient, but the nonspecificity of these symptoms always warrants further testing. In the post acute phase of an illness-in the chronically ventilated patient, in particular-symptoms of PE, such as dyspnea, anxiety, pleuritic chest pain, or hemoptysis, are all too common. These symptoms often can reflect the presence of other conditions such as pneumothorax, pneumonia, pleurisy, ventilator-associated peneumonia, exacerbation of chronic obstructive lung disease, or congestive heart failure. In this particular setting of a protracted illness, PE can add significantly to morbidity and mortality when left undiagnosed. Unfortunately, there are no reported data on the exact impact of PE in this patient population. Such information is needed greatly considering the fast-growing population of chronically ill patients on assisted ventilation that is present in various clinical settings throughout the country.

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Natural History

Clinical Presentation

Pulmonary emboli arise when a thrombus Autopsy studies indicate that both DVT in the venous peripheral circulation dislodges and PE often remain u n d i a g n ~ s e dThe . ~ ~nonand travels to the pulmonary circulation, obspecific symptoms and signs of these entities structing blood flow. Most often, a small em- . and the fact that small emboli can be clinically bolus occludes a distal pulmonary vessel; silent most likely account for this finding. larger emboli tend to obstruct the main stem Although, as noted, most PEs arise from the deep veins of the lower extremities, only one pulmonary arteries. Occasionally, a large emthird of patients with PE have clinical signs bolus occludes the bifurcation of the main of DVT. Similarly, 50% of patients diagnosed pulmonary artery (saddle embolus), leading with proximal DVT have asymptomatic PEs to catastrophic hemodynamic consequences. at pre~entation.~~ The most reliable symptom Greater than 90% of PEs result from DVTs in patients with significant PE is dyspnea of that arise in the lower extremities.18The risk acute onset.35This symptom can be transient for PE from an untreated proximal leg DVT in nature but is usually more severe when the is SO%, as opposed to 15% to 30% from the embolus is larger. Other symptoms seen at calf veins., In the latter case, there is usually presentation are diaphoresis, dizziness, hepropagation of the thrombus to the proximal moptysis, pleuritic chest pain, and, less freleg veins before embolization to the pulmoquently, syncope.lo4Pleuritic chest pain, tonary vasculature. The fact that the lower exgether with hemoptysis, suggest a pulmonary tremities are the major source of PEs makes infarction. Symptoms commonly thought to the prevention of DVT a crucial aspect in be typical, such as dyspnea, chest pain, and decreasing the incidence of PE. Other less leg pain or swelling, are only present in 50% frequent sources of thrombi include the veins of the upper extremities, pelvis, and abdoof patients, however.36,Io4 Furthermore, in the chronically ill and ventilated patient, these men, and the right side of the heart. The use symptoms may be masked or may reflect the of indwelling catheters for chemotherapy or occurrence of other pathologies. Occasionally, nutrition has led to an increased risk for PE that is estimated to be as high as 20% in the frequent need for adjustment in ventilator patients with symptomatic arm vein thromsettings or increased ventilator dependence in bosi~.~~ a patient who was otherwise in the process Besides mechanical obstruction of the pulof being weaned can be attributed wrongly monary circulation, several other factors, into other conditions (e.g., a flare of chronic cluding humoral mediators, such as serotonin obstructive disease, mucous plugging, or venand thromboxane-A,, are released by actitilator-associated pneumonia) when, in fact, vated platelets and are thought to contribute an underlying PE may be present. to the elevated pulmonary artery pressure The physical signs most reliably found in seen with PE by causing vasoconstriction.35If PE are tachypnea and tachycardia, and they the resulting pulmonary hypertension is sealso can be transient.lo4In addition to these vere or there is a history of underlying lung physical signs, the patient may be febrile disease, the patient is at risk for developing (usually < 101°F) or even hypotensive if the embolism is massive. Lung examination may right ventricular (RV) strain, with subsequent RV failure and death. Patients who die from appear normal or reveal rales, a pleural fricPE usually do so early, however, and those tion rub, or decreased breath sounds in areas who survive the initial diagnosis usually do of atelectasis or a pleural effusion. Rarely, not die as a result of the initial embolus. It is a patient can have wheezing secondary to known now that death in these patients is bronchoconstriction of the affected lung or a usually secondary to an underlying maligmurmur secondary to incomplete blockage of nancy or cardiac or pulmonary disease, or as a large pulmonary vessel. Cardiac examination, with the exception of tachycardia, is usua result of repeated embolization in the first 2 weeks after the initial onset of PE.,l Although ally normal. If there is major obstruction of epidemiologic studies are not yet available, it the pulmonary circulation, signs of acute cor is likely that PE is a major source of morbidity pulmonale can be present, including cannon and mortality for the patient in the post acute a waves in the jugular venous pulse, a left and protracted phase of a medical or surgiparasternal heave, a right-sided S, gallop, a cal illness. pulmonic valve murmur, a loud Pz, or a wide

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fixed splitting of the second heart sound. In the chronically critically ill patient, pre-existing physical findings often render the physical examination difficult to interpret. In situations suggestive of PE, diagnostic efforts should be pursued dcspite alternative explanations because undiagnosed PE may be fatal. It therefore is important to combine clinical suspicion with diagnostic testing (such as ventilation-perfusion scanning), as has been suggested, in general, for the accurate diagnosis of PE.48An algorithm, such as that shown in Figure 2, may help in the diagnosis of PE.

Electrocardiography

The electrocardiograph (ECG) most often reveals tachycardia, but a right ventricular strain pattern may be identified in a minority of patients. This strain pattern can include right axis deviation, p pulmonale or an S1Q3T3 pattern (prominence of S wave in lead I, Q wave in lead 111, and T wave inversion in lead 111). In patients without pre-existing cardiopulmonary disorders, a normal ECG is obtained in 23% of patients with submassive PE and in 6% with massive I’ES.~~In general, for the diagnosis of PE and, in particular, in chronically ill patients who have a high prevalence of other ECG abnormalities, this and other laboratory tests, such as the chest roentgenogram and arterial blood gases, have little diagnostic value.

Arterial Blood Gas Analysis

Hypoxemia, although common in acute PE, is not universally present. Data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) indicated that, among patients without pre-existing cardiopulmonary disorders, no difference was present in the arterial partial pressure of oxygen (PaoJ or the alveolar-arterial gradient for patients who had PE at angiography compared with patients who had a negative angioPatients with and without PE therefore cannot be distinguished on the basis of PaoPor alveolar arterial gradient.98An abnormal Paoz sometimes indicates the severity of the embolism if the patient does not have underlying cardiopulmonary disease. In the chronically critically ill patient, these values

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are even less meaningful. A significant and unexplained change in oxygen requirement in the absence of another obvious cause should alert the clinician to the possibility of a thromboembolic event, however. Chest Radiography

In 10% to 15% of patients with PE, there are no detectable changes on the chest radiograph.94, Patients with unchanged radiographic results have a higher Paoz and a lower mean pulmonary arterial pressure than patients who have abnormal radiographic res u l t ~Common .~~ radiographic changes related to PE include the classic finding of hyperlucency and decreased vascularity caused by local oligemia (Westermark’s sign), atelectasis with elevation of the hemidiaphragm, and pleural-based areas of increased opacity (Hampton’s hump). The usefulness of these findings generally is limited by poor sensitivity and specificity.lloSimilarly, enlargement of a major pulmonary artery (Fleischner’s sign) and a small pleural effusion49are suggestive of PE but also are uncommon. A normal chest radiograph in a symptomatic ventilated patient with sudden hypoxemia and without evidence of bronchospasm or other airway problem, such a s mucous plugging, is strongly suggestive of PE. This occurrence is rare, however, because pre-existing chest radiograph abnormalities are generally common in chronically ill patients. A chest radiog r a p h usually is ordered routinely for conditions of unexplained dyspnea, increased cough, tachycardia, and hypoxemia to rule out obvious conditions such as a pneumothorax, atelectasis, or a new infiltrate. Again, further testing is recommended when a diagnosis of VTE is suspected on clinical grounds. D-Dimer

D-dimer is a specific degradation product of cross-linked fibrin that is released into the circulation as a result of endogenous fibrinolysis. The use of D-dimer in the diagnosis of VTE has been assessed in many studies using either enzyme-linked immunosorbent assay or latex agglutination techniques (for review, see reference 10a). A low plasma D-dimer level (< 500 ng/mL) has a good (> 95%) negative predictive value for

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PE. Low levels are unlikely to be found in a population of patients with a protracted illness, however. Levels of plasma D-dimer may be elevated in patients with a systemic illness, such as cancer or sepsis, or in patients several days or weeks following a surgical procedure. The D-dimer test therefore has limited value for this group of patients. Furthermore, this test is not recommended as a standard part of the workup for VTE.'O' Ventilation-Perfusion Scanning

The ventilation-perfusion (V/Q) scan is often the first screening test and long has been considered the key noninvasive diagnostic test in patients with suspected PE. It has the benefit of being noninvasive and relatively inexpensive. The PIOPED s t u d y determined the sensitivity and specificity of V/Q scanning by comparing it with the gold standard of pulmonary angiography. Data from this study indicated that 98% of patients with clinically important PE had an abnormal V/Q scan. Therefore, V/Q scanning is a sensitive overall screening test for patients suspected of having PE.48The specificity of a high-probability scan was 97% in the PIOPED study, and all patients with this scan result who had normal angiograms had prior histories of emboli or cancer with vascular involvement. Unfortunately, the high-probability scan only had a sensitivity of 41%; therefore, if high-probability scans were used alone, the diagnosis of PE would have been missed in as many as 59% of patients with clinically significant PE. A near-normal scan made the diagnosis of PE unlikely, whereas the most frequent (39%) scan result, an intermediate scan, was not helpful in making the diagnosis and was seen in 21% to 30% of patients with PE. Combining clinical suspicion with V/Q test results was found to be helpful in making a noninvasive diagnosis or excluding PE in only a minority of patients, but improved the overall chance of reaching a correct diagnosis of PE. Although a lowprobability V/Q scan with a low clinical suspicion of PE made the likelihood of PE remote (4%), for example, a low-probability scan with an intermediate or high clinical suspicion was found in 15%and 4U%, respectively, of patients with PE on angiography. An indeterminate scan or a low-probability scan combined with a high clinical suspicion therefore requires further testing, such as noninvasive

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imaging of the lower extremities or pulmonary angiography. For all practical purposes, all patients with high-probability scans can be treated with anticoagulation without further need for an invasive test, especially when there is high clinical suspicion. Conversely, for near-normal and low-probability scans combined with low clinical suspicion, alternate diagnoses should be sought. In all other situations, V/Q scanning should be considered as nondiagnostic and further tests should be performed. The usefulness of the V/Q scan is more questionable in the chronically critically ill patient on mechanical ventilation because of the likely presence of pre-existing cardiac or pulmonary disease. In the PIOPED study, the prevalence of intermediate-probability scans was highest in patients with cardiopulmonary d i ~ e a s eThis . ~ finding was particularly the case for patients with COPD, in whom 60% had intermediate-probability scans. By extension, it is likely that a large number of patients with complex diseases who are on mechanical ventilation will fall in the scan category (i.e., intermediate-probability scan) in which further testing is required for the diagnosis of PE. It should be noted, however, that the positive predictive value of low, intermediate, and high probability seems to be the same in patients with or without cardiopulmonary disease.95 Several studies have examined the usefulness of serial noninvasive examinations in patients with suspected PE and indeterminate lung scans. In one study evaluating patients with low or intermediate probability lung scans and normal cardiac function, patients who had six consecutive normal IPGs in 2 weeks did well without anticoagulation, suggesting that their risk for significant embolic events was l0w.5~A retrospective study found that adding IPG to clinical assessment and lung scanning reduced the need for angiography from 72% to 33% of patients with suspected PE.97Serial noninvasive lower extremity studies offer the opportunity to follow conservatively a patient with a nondiagnostic lung scan. This approach has been shown to reduce the need for pulmonary angiography1O4and to be co~t-effective.~~ Such a strategy implies that the patient be stable from a respiratory and hemodynamic standpoint, howevez Echocardiography Hemodynamically significant PE may cause characteristic echocardiographic

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changes in patients without prior cardiopulmunary disease.60These include dilation of the RV and the pulmonary outflow tract, and paradoxical motion of the interventricular septum, reflecting increased pulmonary vascular resistance. In the absence of left ventricular disease, these findings indicate hemodynamically significant PE. Right ventricular dilatation is present in about 70% of patients with acute PE. Paradoxical septal wall motion and dilatation of the pulmonary arteries, however, are more common in patients with pulmonary hypertension than patients with acute or subacute massive PE. Unfortunately, the finding of RV dysfunction is not specific and certain clinical conditions commonly confused with PE (such as acute COPD exacerbation) also are associated with abnormal RV function. Doppler echocardiography, used to evaluate tricuspid regurgitation flow, also allows estimation of the mean pulmonary artery pressure.60If this pressure is greater than 40 mm Hg, then the increased pulmonary vascular resistance is chronic (e.g., caused by chronic PE). In general, echocardiography is not used routinely in the diagnosis of thromboembolic disease. This noninvasive test occasionally detects a clot in the right heart cavities or in a main pulmonary artery,6 however, which may be sufficient to warrant anticoagulation or thrombolytic therapy in patients who have severe hemodynamic insufficiency. Echocardiography is also useful to follow a patient's progression (i.e., changes in right ventricular dilation or septal motion) once treatment, such as thrombolysis, is instit~ted.~~ Transesophageal echocardiography is more sensitive than transthoracic echocardiography, and recent studies have indicated that this type of echocardiography may be more useful for detecting clots in the main or right76 pulmonary arteries. In summary, echocardiography offers the advantages of being performed at the bedside, but its usefulness as a routine test in the diagnosis of PE needs to be further determined. Spiral Computed Tomography

Spiral CT scanning was introduced recently for the diagnosis of both acute and chronic PE. Contrast material needs to be injected for visualization of the pulmonary vessels. Sensitivity and specificity greater than 95% for clots located in the main, lobar, and segmental pulmonary arteries have been re-

ported for this technique.86,lo5 The sensitivity of spiral CT is significantly less for subsegmental emboli38that, however, do not represent a large proportion of PE (only 6% according to data from the PIOPED study).* In addition to visualizing the pulmonary vasculature, spiral CT has the advantage of assessing the mediastinal structures and the pulmonary parenchyma. Limitations of spiral CT scanning include poor visualization of the peripheral areas of the upper and lower lobes and of the subsegmental arteries. Lymph nodes occasionally may cause false-positive results. The exact role of spiral CT scanning needs to be determined in large clinical trials. Such trials are being conducted in Europe and planned in the United States.lol Magnetic Resonance Imaging

Magnetic resonance imaging is being investigated for its role in diagnosing PE. In a small prospective study of 30 patients with suspected PE, gadolinium-enhanced MR imaging angiography was shown to be both sensitive and specific compared with angiograMagnetic resonance imaging offers some advantages over angiography, such as its noninvasive nature and avoidance of nephrotoxic contrast material. The high cost, limited availability in intermediate and chronic care facilities, and the problem of metallic devices, however, restrict the utility of MR imaging in chronically critically ill patients. Pulmonary Angiography

Pulmonary angiography remains the gold standard for the diagnosis of PE. A contrast medium is injected through a catheter into the right or left pulmonary artery. Pulmonary embolism is diagnosed angiographically by the presence of an intraluminal filling defect in two views or the demonstration of total obstruction of a pulmonary vessel by a clot. Secondary criteria are nonspecific and include reduced perfusion and flow, tortuous peripheral vessels, and delayed venous return.= The study allows visualization of the arterial tree and measurement of pulmonary artery pressures. A pulmonary angiogram is usually ordered when the V/Q scan is nondiagnostic but the clinical suspicion remains high. Pulmonary angiography for the diagnosis of acute PE is unnecessary in a patient with a

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vated partial thromboplastin time (APTI’).The normal perfusion scan.7 The test also may be goal of therapy is to achieve an APTT that is unnecessary in a patient with a high-probability V/Q scan and in whom the clinical suspi1.5 to 2 times greater than the control value within 24 hours after instituting therapy. This cion is high because the likelihood of PE is range of activated partial thromboplastin time high (greater than 90%) and anticoagulation has been shown to allow effective anticoagugenerally is recommended in such context. lation while minimizing bleeding complicaDisadvantages of pulmonary angiography intions. Failure to achieve therapeutic levels clude its invasiveness, cost, and the need for within 24 hours has been shown to result in experienced staff. Relative contraindications an increased risk for recurrent The use include significant bleeding risk and renal inof an intuitive approach for heparin dosing sufficiency. The presence of a left bundle has been found to be inadequate, and differbranch block may be an indication for placeent nomograms have been developed to aid ment of a temporary pacemaker during the physicians in intial heparin dosing and in procedure to protect against complete heart dose t i t r a t i ~ n . ~ ~ block. Intravenous heparin should be used in conPulmonary angiography carries a mortality junction with warfarin for an overlap period rate of 0.2% to 0.5% and a morbidity rate of of 4 to 5 days because prothrombin depletion 5%, most often secondary to contrast reacdelays the antithrombotic effect of intraveIn the PIOPED tions or catheter in~ertion.~ nous heparin for this time period. A prospecstudy, 5 of 1111 patients died in the setting tive analysis comparing treatment using hepof pulmonary angiography. These patients all arin and warfarin with treatment using were referred from intensive care units, however, and were considered to be m0ribund.9~ warfarin alone in patients with DVT showed that extension of the thrombosis occurred in Aside from death, severe complications in8% of patients who received the combination clude cardiopulmonary instability, requiring therapy and in 40% of patients who received intubation or resuscitation; renal failure, rewarfarin a10ne.l~Recent studies have shown quiring dialysis; or groin hematomas, requirthat a lower therapeutic range of warfarin ing blood transfusion. Elevation in serum cre(i.e., a prothrombin time [PT] of 1.25 to 1.5 atinine, not requiring dialysis, occurred in times the control level or an International 0.9% of ~atients.9~ Aside from renal insuffiNormalized Ratio [INRI of 2 to 3) is still effecciency, there does not appear to be increased tive for preventing recurrent thromboses risk for significant complications related to while minimizing bleeding risks.” Warfarin age when pulmonary angiography is perusually is administered at a dose of approxif0rrned.9~In most stable patients with commately 5 mg and the dose is adjusted deplex medical diseases on chronic ventilation, pending on the INR. Once the INR is stable, pulmonary angiography therefore appears weekly testing should be performed for the reasonably safe. As a rule, the risk for angiogfirst few weeks of therapy; if the INR readings raphy by experienced physicians is less than are stable, testing can be performed over the risk for anticoagulant therapy? Angiogralonger intervals of time. phy, rather than empiric anticoagulation, Prolonged anticoagulation therapy is necestherefore is recommended in patients with sary to prevent recurrent thromboembolism. indeterminate noninvasive studies. In genTreatment with warfarin for DVT is known eral, when a definitive diagnosis is necessary, to decrease significantly the risk for recurrent the benefit of the procedure outweighs the venous VTE.50Recent randomized trials have risk.lo1 helped provide guidelines on the duration of anticoagulation needed for different patient TREATMENT populations.= For patients with a first occurrence of proximal DVT and PE, 3 to 6 months of warfarin treatment is recommended. Anticoagulation Shorter courses of anticoagulation are associated with significantly higher rates of recurAnticoagulation, initially with heparin and rence. Lifelong anticoagulation is recomsubsequently with warfarin, has been the cormended for patients with recurrent DVT or nerstone of treatment for DVT and PE since PE, and for patients with irreversible risk facthe 1960s. Heparin initially is administered intravenously to therapeutic levels and foltors, such as Factor V Leiden, antiphospholipid antibodies, or malignancy. Patients with lowed by measurement of a patient’s acti-

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transient risk factors, such as trauma or orthopedic surgery, may require anticoagulation either for 4 to 6 weeks or until the risk factor is eliminated. The main risks of heparin and warfarin treatment are bleeding complications, occurring in roughly 8% of patients on heparin Contrary and in 4% of patients on to popular belief among physicians, a supratherapeutic APTT never has been shown to cause an increased risk for bleeding. Rather, this complication is thought to be better correlated with the patient's underlying risk factors for bleeding, such as older age or baseline t h r o m b ~ c y t o p e n i a .In ~ ~ the case of warfarin, however, the risk for bleeding is correlated directly to the dose intensity as measured by the PT or INR. Patients with malnutrition, underlying hepatic or renal disease, or who are receiving drugs that can interact with warfarin (such as antibiotics), may be more sensitive to warfarin's effects and therefore must be followed closely. Low molecular weight heparins (LMWHs) recently have been the subject of many clinical trials. Several preparations have been evaluated in clinical trials and are listed in Table 2. The only agents approved in the United States for prophylaxis of DVT are enoxaparin and dalteparin, ardeparin, and danaparoid. Low molecular weight heparins are prepared by depolymerization of standard unfractionated heparin and, as a consequence, have better bioavailability, a longer half-life, and more predictable anticoagulation effect. These differences translate into similar anticoagulation effects with possibly fewer bleeding risks than standard heparin. In addition, these properties enable LMWH to be dosed according to patient weight and Table 2. LOW MOLECULAR WEIGHT HEPARIN PREPARATIONS Generic Name

Trade Name

Dalteparin* Enoxaparin" Ardeparin* Tinzaparin Innohep Nadroparin Certroparin Pamaparin Reviparin Danaparoidt

Fragmin Loven ox Normiflo Logiparin Leo Fraxiparin Sandoparin Flaxum Clivarin Orgaran

*Approved for DVT prophylaxis in the United States. tHeparinoid preparation; indicated in cases of heparin-induced thrombocytopenia; not FDA approved for DVT prophylaxis.

given subcutaneously without the need for laboratory testing. Several randomized trials have shown that fixed doses of LMWH are as effective as adjusted doses of intravenous heparin for treating DVT.33Studies also have indicated that patients with proximal DVT could be safely and effectively treated at home with LMWH.64,66 The elimination of laboratory testing, the potential decreased need for hospitalization and the decreased recurrence of thromboses may translate into overall cost reduction. In addition, LMWHs have been the focus of many prophylaxis trials and have been shown to be superior to standard heparin in efficacy and safety in patients undergoing orthopedic and general surgery, in highrisk geriatric patients, and in patients with spinal cord injury.lo0Adverse effects are similar to standard heparin and include bleeding, thrombocytopenia, and osteoporosis if used for prolonged periods. Vena Cava Interruption

Vena cava filter devices are indicated for patients with contraindications to anticoagulation therapy, patients who have failed anticoagulation, and patients who are at high risk for mortality from recurrent PE. Vena cava filters usually are inserted percutaneously into the inferior vena cava (IVC) at a level below the renal veins. This location serves to trap emboli from the lower extremities while maintaining blood flow through the IVC. Five IVC filters are available in the United States: (1) Greenfield (stainless steel); (2) Greenfield (titanium) (Medi-tech/Boston Scientific Corp., Watertown, MA); ( 3 ) Bird's Nest (Cook, Bloomington, IN); (4) Simon-Nitinol (Nitinol Medical Tech, Woburn, MA); and (5) Vena Tech (Venatech, Evanston, IL). No filter has been proved superior to any other filter, and the actual effectiveness of IVC filters is unknown given the lack of randomized tria l ~Based . ~ on case studies, the recurrence of PE after an IVC filter is roughly 3% and death from recurrent PE is less than l%.9 Complications caused by IVC filter placement include DVT, filter migration, IVC perforation or obstruction, lower extremity edema, and infection. Patients who do not have contraindications often receive anticoagulation after filter placement. This practice is thought to prevent DVT at the insertion site, IVC thrombosis, and the propagation of clot from an occluded filter.

MANAGEMENT OF VENOUS THROMBOEMBOLIC DISEASE

Thrombolytic Therapy

The indications for thrombolytic therapy are a massive ileofemoral DVT or a massive PE. Thrombolytic therapy for PE accelerates clot lysis and therefore decreases pulmonary artery pressures and the consequent RV dysfunction that can result in death. Despite improvements in hemodynamics, lung scanning, echocardiography, and angiography after thrombolytic treatment, no evidence from any prospective trials has shown that lytic therapy improves survival in acute PE compared with standard therapy with heparin. This failure to detect significant changes in mortality may be secondary to the small size of these trials. Thrombolytic therapy also may lead to improved pulmonary function and exercise tolerance after recovery and more rapid reso90 For lution of V/Q scanning abn~rmalities.~~, DVT treatment, thrombolysis results in more rapid venographic resolution of thrombus, but there are no data demonstrating a reduction in the post-phlebitic syndrome. The three thrombolytic agents approved for acute PE in the United States are urokinase, streptokinase, and tissue plasminogen activator. The recommended dosing regimens are shown in Table 3. No one agent has been found to be superior in efficacy or safety. Thrombolytic therapy should be administered within 24 hours of a PE, and heparin is started once the APTT falls below 80 seconds. Angiography is recommended to confirm the diagnosis of PE before therapy but may not be required in patients with high clinical suspicion and high-probability V/Q scans. In hemodynamically unstable patients, an emergent bedside ECG occasionally visualizes a clot in the main pulmonary outflow tract or Table 3. THROMBOLYTIC AGENTS APPROVED BY THE UNITED STATES FOOD AND DRUG ADMINISTRATION FOR THE TREATMENT OF PULMONARY EMBOLISM Agent

Streptokinase Urokinase Recombinant tissue plasminogen activator

Dose

250,000 U loading dose over 30 minutes, followed by 100,000 U/hour for 24 hours 4400 U/ kg over 10 minutes, followed by 4000 U/ kg for 12-24 hours 100 mg continuous intravenous infusion over 2 hours

Data from Urokinase Pulmonary Embolism Trial Phase 1 results: A cooperative study. JAMA 2142163-2172,1970.

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shows evidence of RV strain. Indication for thrombolytic therapy may be based on these findings. In patients who are stable and with indeterminate V/Q scans, however, angiography should be done before instituting lytic therapy. The incidence of significant bleeding in patients with DVT who are treated with thrombolytics is between 6% and 30%, a threefold increase compared with heparin alone. The incidence of major bleeding in patients with PE treated with thrombolytics ranges between 5% and 20% and is usually catheter related; fatal hemorrhage occurs in 1%to 2%. Contraindications for lytic therapy include: major bleeding within the prior 6 months, intracranial or intraspinal disease, aneurysm, surgery within the preceding 10 days, pericarditis, uncontrolled hypertension, pregnancy, and endocarditis. Given the lack of clear-cut evidence regarding the benefits of thrombolytic treatment and the significant incidence of bleeding complications, thrombolytic therapy should be reserved for selected patients with PE; those who are hemodynamically unstable, patients with a large burden of clot occluding over one half of the pulmonary vasculature, and young patients with significant vascular compromise secondary to a large DVT. PROPHYLAXIS

The problem of VTE and its impact on health care cannot be underestimated. More than 5 million episodes of DVT occur annually in the United States, leading to about 500,000 cases of PE of which 10% are fatal.70 Prophylactic treatment, in particular in hospitalized patients, therefore is essential to reduce the morbidity and mortality of this disease. Although the benefits of prevention have been established mainly in surgical patients, there is a growing body of evidence that prevention is effective in medical patients as well. Prophylaxis now has been shown to be effective and safe in preventing VTE in patients with myocardial infarction,30,Io6 ischemic 79 heart failure, and strokerMcritical illne~s,'~, respiratory infecti0n.l' Although no study has been performed in patients in intermediate care facilities, prevention of thromboembolism would seem to be safe and beneficial for this patient population, who often have a number of risk factors for this disease. In the surgical population, DVT prophylaxis has

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been shown to be cost effective.77,78 This finding is particularly the case when prevention is compared with medical intervention limited to thromboembolism that becomes clinically apparent.53 Despite the proved efficacy of DVT prophylaxis, it seems that high-risk patients at teaching and nonteaching hospitals often receive inadequate DVT pro phyla xi^.^^ For this reason, consensus guidelines have been developed to aid physicians in determining adequate prophylaxis for patients. Table 4 summarizes the current prophylaxis regimens recommended by a number of consensus g~idelines.~~ The methods of prophylaxis can be divided into physical and pharmacologic. Physical methods aim at decreasing venous stasis and include elastic and graduated compression stockings, intermittent pneumatic compression, and early ambulation. The pharmacologic measures include administering subcutaneous low-dose standard heparin or LMWH, warfarin, and antiplatelet drugs. The Table 4. PROPHYLAXIS FOR VENOUS THROMBOEMBOLISM IN MEDICAL AND SURGICAL PATIENTS Patient Population Medical patients Stroke, hemorrhagic Stroke, nonhemorrhagic Acute myocardial infarction or congestive heart failure Acute spinal cord injury

Surgical patients Low risk (short anesthesia, age < 40 years old, no risk factors) High risk (age > 40 years old, major surgery, risk factors present) Elective orthopedic surgery Surgery to correct hip fracture Neurosurgery

Surgery for multiple trauma-induced injuries

Prophylaxis Intermittent pneumatic compression Low-dose heparin Low-dose heparin Low molecular weight heparin or adjusted dose of unfractionated heparin

No prophylaxis

Graduated compression stockings and low-dose heparin or low molecular weight heparin Low molecular weight heparin or warfarin Low molecular weight heparin or warfarin Intermittent pneumatic compression or graduated compression stockings Intermittent pneumatic compression

recommendations depend on the type of surgery or the patient’s underlying risks for thrombosis, such as prolonged bed rest. Intermittent pneumatic compression, which has been shown to be an effective mode of prohas not been phylaxis in surgical studied in medical patients. Pneumatic compression devices have a fibrinolytic effect aside from augmenting venous return from the e~tremities.’~, 71, Io9 They are available in different compression types, such as the multichamber sequential pressure devices that are believed to be superior to the nonsequential models. There has not been any clinical study to support this theory, however. Whatever mechanical compression device is used, careful daily inspection of the lower extremities is needed to avoid skin injury by the apparatus. @

Deep Venous Thrombosis Prophylaxis for Patients with Spinal Cord Injury

Prevention of VTE in patients with spinal cord injury (SCI) represents a particular problem. Several acquired risk factors play a role in the increased incidence of VTE in SCI, including venostasis, a transient hypercoagulable state, and abnormalities of hemostasis.”, 73, 58, 89 Pulmonary embolism is among the leading causes of death in patients with paraplegia, accounting for 14.9% in all patients with SCI, in the first postinjury year.27,99 The incidence of DVT in patients with SCI left without medical prophylaxis is increased significantly in the first 2 weeks after injury and declines after 8 weeks. The exact long-term incidence of DVT in these patients is unclear.42, The choice of prophylaxis in SCI is guided by the degree of disability of the patient and the presence of associated medical conditions that may represent added risk factors. Patients are categorized into either motor incomplete, motor complete, or motor complete injury with other risks for VTE.41 All patients with SCI should be on anticoagulation prophylaxis, if feasible, for at least the first 8 to 12 weeks following injury, depending on the level of disability.l6T39* 83 The preferred anticoagulation method is LMWH or adjusted-dose heparin. Both methods have been proved to be more effective prophylactic treatments than low-dose unfractionated heparin or the combination of compression devices and antiplatelet agents.31,4-, 45, 48 If pro-

MANAGEMENT OF VENOUS THROMBOEMBOLIC DISEASE

phylaxis is delayed for more than 72 hours, lower extremity Doppler studies should be performed if intermittent compression devices are to be used. The duration of prophylaxis also should be individualized for every patient, and the benefits of long-term use of heparin prophylaxis should be carefully weighed against the potential risks of such therapy. Patients at a high risk for bleeding or with conditions prohibiting the use of anticoagulation should be considered for prophylaxis with mechanical devices.68,71,lo9 Anticoagulation therapy should be started as soon as feasible. Combining external compression devices with anticoagulation therapy has been shown to decrease the incidence of DVT in patients with SCI.4” Mechanical modalities other than compression devices are used to reduce the incidence of DVT in patients with SCI. Examples include active and passive range of movement and centripetal massaging. Early mobilization and physical therapy should be initiated as soon as possible. The effectiveness of all these mechanical methods has not been tested, however, and the recommendation for their use essentially is based on uncontrolled reports. Deep Venus thrombosis prophylaxis eventually can be discontinued in patients with SCI after the acute period is over and more patient mobility is regained. Prophylaxis should be immediately reinstituted in these patients in case of an intervening acute medical illness, if patients are left immobilized in bed, or if they are readmitted to an acute care facility. Readmission to acute care hospitals has been recognized as a risk factor for DVT in patients with SCI. The incidence of DVT in these patients is 16.6% in complete motor injury patients, 12.5% in incomplete motor injury, and 6.4% for patients with minimal deficit. SUMMARY

Although PE is the most common preventable cause of death among U.S. hospital patients, proper treatment of thromboembolism and adequate prophylaxis in high-risk patients have been shown to be effective in saving lives. Because clinical symptoms and signs of thromboembolic disease are often nonspecific, early diagnosis and treatment rely on the capacity of physicians to adequately identify a patient at risk, choose the appropriate diagnostic modalities in a cost-

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effective fashion, and promptly initiate treatment. The diagnosis of VTE is particularly challenging in patients who are in the post acute period of a complex medical or surgical illness. Avenues that need to be further explored include various diagnostic tests such as spiral CT, M R imaging, and transesophageal echocardiography, which are less invasive than the present gold standard of pulmonary angiography. Also needed are better clinical data regarding the optimal choice of preventive therapy (e.g., unfragmented heparin or LMWH or mechanical devices) and clinical outcome of such therapy in patients with prolonged illness. References 1. Agnelli G, Cosmi B, Radicchia S, et a1 Features of thrombi and diagnostic accuracy of impedance plethysmography in symptomatic and asymptomatic deep vein thrombosis. Thromb Haemost 70:266269, 1993 2. Alpert JS, Smith R, Carlson J, et al: Mortality in patients treated for pulmonary embolism. JAMA 2361477-1480, 1976 3. Anderson FA Jr, Wheeler HB Physician practices in the management of venous thromboembolism: A community-wide survey [see comments]. J Vasc Surg 16707-714, 1992 4. Anderson FA Jr, Wheeler HB: Venous thromboembolism. Risk factors and prophylaxis. Clin Chest Med 16235251,1995 5. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al: A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 151:933-938,1991 6. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al: Changing clinical practice. Prospective study of the impact of continuing medical education and quality assurance programs on use of prophylaxis for venous thromboembolism. Arch Intern Med 154669677, 1994 7. Anonymous: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators [see comments]. JAMA 263:2753-2759, 1990 8. Baker WF Jr, Bick R L Treatment of hereditary and acquired thrombophilic disorders. Semin Thromb Hemost 25:387406, 1999 9. Ballew KA, Philbrick JT, Becker DM: Vena cava filter devices. Clin Chest Med, 16:295-305, 1995 10. Baxter GM, Kincaid W, Jeffrey RF, et al: Comparison of colour Doppler ultrasound with venography in the diagnosis of axillary and subclavian vein thrombosis. Br J Radio1 M777-781, 1991 10a. Becker DM, Philbrick JT, Bachhuber TL, Humphries JE: D-dimer testing and acute venous thromboembolism. A shortcut to accurate diagnosis? Arch Intern Med 1996; 156:93946. 11. Belch JJ, Lowe GD, Ward AG, et al: Prevention of

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deep vein thrombosis in medical patients by lowdose heparin. Scott Med J 26115-117, 1981 12. Bertina RM: The prothrombin 20210 G to A variation and thrombosis. Curr Opin Hematol 5:339342, 1998 13. Bertina RM, Rosendaal FR Venous thrombosis-the interaction of genes and environment [editorial comment]. N Engl J Med 338:1840-1841,1998 14. Birdwell BG, Raskob GE, Whitsett TL, et al: The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 12%-7, 1998 15. Borgstede JP, Clagett GE: Types, frequency, and significance of alternative diagnoses found during duplex Doppler venous examinations of the lower extremities. J Ultrasound Med 11:85-89, 1992 16. Brach BB, Moser KM, Cedar L, et a1 Venous thrombosis in acute spinal cord paralysis. Journal of Trauma-Injury Infection & Critical Care 17289-292, 1977 17. Brandjes DP, Heijboer H, Buller HR, et al: Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 3271485-1489, 1992 18. Browse NL, Thomas M L Source of non-lethal pulmonary emboli. Lancet 1:258-259, 1974 19. Cade JF: High risk of the critically ill for venous thromboembolism. Crit Care Med 10:448-450, 1982 20. Carpenter JP, Holland GA, Baum RA, et al: Magnetic resonance venography for the detection of deep venous thrombosis: Comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg 18734-741, 1993 21. Carson JL, Kelley MA, Duff A, et al: The clinical course of pulmonary embolism [see comments]. N Engl J Med 326:1240-1245,1992 22. Cattaneo M, Monzani ML, Martinelli I, et al: Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism [letter comment]. Circulation 97295-296, 1998 23. Chambers JC, McGregor A, Jean-Marie J, et al: Acute hyperhomocysteinaemia and endothelial dysfunction [letter]. Lancet 351:36-37, 1998 24. Cog0 A, Lensing AW, Koopman MM, et al: Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: Prospective cohort study [see comments]. BMJ 316:17-20, 1998 25. Comerota AJ, Chouhan V, Harada RN, et al: The fibrinolytic effects of intermittent pneumatic compression: Mechanism of enhanced fibrinolysis. Ann Surg 226:306-313; discussion, 226:313-314, 1997 26. den Heijer M, Rosendaal FR, Blom HJ: Hyperhomocysteinemia and venous thrombosis: A meta-analysis. Thromb Haemost 80:874-877, 1998 27. DeVivo MJ, Stover SL: Long-term survival and causes of death. In Stover SL, DeLisa JA, Whiteneck GG (eds): Spinal Cord Injury: Clinical Outcomes From the Model Systems. Gaithersburg, Aspen Publishers, 289-316, 1995 28. Erdman WA, Jayson HT, Redman HC, et al: Deep venous thrombosis of extremities: Role of MR imaging in the diagnosis. Radiology 174:425431, 1990 29. Evans AJ, Sostman HD, Witty LA, et al: Detection of deep venous thrombosis: Prospective comparison of MR imaging and sonography. J Magn Reson Imaging 6:44-51, 1996 30. Gallus AS, Hirsh J, Tutle RJ, et al: Small subcutaneous doses of heparin in prevention of venous thrombosis. N Engl J Med 288:545-551, 1973

31. Geerts WH, Jay RM, Code KI, et al: A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma [see comments]. N Engl J Med 335:701-707, 1996 32. Gelernt MD, Mogtader A, Hahn RT Transesophageal echocardiography to diagnose and demonstrate resolution of an acute massive pulmonary embolus. Chest 102:297-299, 1992 33. Ginsberg JS: Management of venous thromboembolism [see comments]. N Engl J Med 335:1816-1828, 1996 34. Ginsberg JS, Caco CC, Brill-Edwards PA, et al: Venous thrombosis in patients who have undergone major hip or knee surgery: Detection with compression US and impedance plethysmography. Radiology 181:651459, 1991 35. Goldhaber SZ: Managing pulmonary embolism. Hospital Practice (Office Edition) 26:3748, 1991 36. Goldhaber SZ, Hennekens CH, Evans DA, et al: Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med 73S22-826, 1982 37. Goldhaber SZ, Kessler CM, Heit J, et al: Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 2:293-298, 1988 38. Goodman LR, Curtin JJ, Mewissen MW, et al: Detection of pulmonary embolism in patients with unresolved clinical and scintigraphic diagnosis: Helical CT versus angiography. AJR Am J Roentgen01 164:1369-1374, 1995 39. Green D, Biddle A, Fahey V, et al: Prevention of thromboembolism in spinal cord injury. Consortium for Spinal Cord Medicine. J Spinal Cord Med 20~259-283, 1997 40. Green D, Lee MY, Ito W, et al: Fixed- vs adjusteddose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA 260:1255-1258, 1988 41. Green D, Lee MY, Lim AC, et al: Prevention of thromboembolism after spinal cord injury using low- molecular-weight heparin [see comments]. Ann Intern Med 113:571-574, 1990 42. Green D, Rossi EC, Yao JS, et al: Deep vein thrombosis in spinal cord injury: Effect of prophylaxis with calf compression, aspirin, and dipyridamole. Paraplegia 20:227-234, 1982 43. Haire WD, Lynch TG, Lieberman RP, et al: Utility of duplex ultrasound in the diagnosis of asymptomatic catheter-induced subclavian vein thrombosis. J U1trasound Med 10:493496, 1991 44. Hajjar KA: Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:28732879, 1993 45. Harris S, Chen D, Green D. Enoxaparin for thromboembolism prophylaxis in spinal injury: Preliminary report on experience with 105 patients. Am J Phys Med Rehabil 75:326-327,1996 46. Hayashi T, Honda G, Suzuki K: An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 79:2930-2936, 1992 47. Heijboer H, Buller HR, Lensing AW, et al: A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients [see comments]. N Engl J Med 329:1365-1369, 1993

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