Deep Venous Thrombosis in the Surgical Intensive Care Unit

Surgical Critical Care

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Deep Venous Thrombosis in the Surgical Intensive Care Unit David B. Hoyt, MD, * and James R. Swegle, MDt

The true incidence of deep venous thrombosis in patients in the intensive care unit (ICU) is not well documented. The original autopsy studies done by Sevitt and Gallager in the early 1960s demonstrated that deep venous thrombosis and pulmonary embolism were commonly unrecognized as clinical entities in the injured patient. 68 The patient population in the surgical ICU has a wide array of complex medical and surgical illness. Most, if not all, of these patients have one or more risk factors that predispose them to deep venous thrombosis and its potential sequelae, including fatal pulmonary embolism. Such emboli are responsible for 12% to 15% of deaths in acute care hospitals, and most patients who die from a pulmonary embolism do so before effective therapy can be instituted. 62 Therefore, a high index of suspicion and a low threshold for diagnostic testing and treatment are required. Essentially all leu patients require some form of prophylaxis. The objectives of prophylaxis and treatment of thrombosis are listed in Table 1. This article will review the etiology, risk factors, diagnosis, prophylaxis, and treatment of deep venous thrombosis and pulmonary embolism, focusing on the ICU patient population.

ETIOLOGY AND PATHOGENESIS An understanding of the proposed etiology and pathophysiology of deep venous thrombosis and pulmonary embolism is helpful in guiding decision-making in regard to prophylaxis and treatment.

*Associate

Professor of Surgery, Chief, Division of Trauma; and Director, Surgical Intensive Care Unit, University of California, San Diego, San Diego, California tClinical Instructor in Surgery, Division of Trauma, University of California, San Diego, San Diego, California

Surgical Clinics of North America-Vol. 71, No.4, August 1991

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Table 1. Objectives of Prophylaxis and Treatment of Deep Venous Thrombosis Prevention of fatal pulmonary embolism Prevention of thromboembolic pulmonary hypertension Prevention of the post phlebitic sequelae Varicosities Recurrent deep venous thrombosis Venous stasis changes Venous claudication

Deep Venous Thrombosis The genesis of a deep vein thrombosis is dependent on many local and systemic factors, venous anatomy, and the time course of the disease process. Virchow (1846 and 1856) described three fundamental factors responsible for venous thrombosis: venous stasis, endothelial (intimal) injury, and hypercoagulability. Stasis. Supine positioning, as occurs with surgery, prolonged immobilization, or paralysis, causes pooling of blood in the soleal sinuses of the calf55 and has long been recognized as a contributing factor. The vasodilatory effects of general anesthesia, sepsis, or any other state that increases venous capacitance and decreases the venous velocity and pulsatile flow in the lower extremity contribute to stasis. 7, 48 Polymorphonuclear leukocyte adhesion, attachment, and activation and subsequent tissue damage are more likely to occur in this setting." Without regular calf-muscle contractions, thrombi can develop in the venous valve CUsps and intramuscular sinuses. Although stasis alone does not produce thrombi, it enhances their development when accompanied by other factors that initiate clot formation (intimal injury or hypercoagulability)."? Intimal (Endothelial) Injury. Endothelial disruption can occur secondary to local factors including direct vessel injury, infection, or inflammation, or to remote tissue injury or general anesthesia, the damage being mediated by the release of vasoactive substances (serotonin, histamine, and bradykinin) that cause a separation of the tight junctions between endothelial cells." After endothelial disruption, thrombogenic subendothelial matrix (basement membrane, extracellular protein) is exposed, and the extrinsic coagulation cascade is activated, with resultant platelet and fibrin adherence. Subsequent platelet release and recruitment of polymorphonuclear cells perpetuate the formation of thrombus. Endothelial surface tears are commonly located around valves and side branches where laminar blood flow is disturbed and turbulence produces high shear forces. 67 Hypercoagulability. Several factors place the injured or postoperative patient at high risk for a transient hypercoagulable state. The factors are difficult to detect and measure with laboratory tests. Increased circulating tissue thromboplastin and activated procoagulants, decreased fibrinolytic activity, ineffective clearance of activated clotting factors by the liver during states of hypoperfusion, and increased platelet aggregation secondary to catecholamine release have all been suggested. 19

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An inherited or acquired hypercoagulable state unrelated to surgery or specific injury also contributes to deep venous thrombosis risk.": 66 Inherited hypercoagulability disorders include antithrombin III deficiency (most common), protein C and protein S deficiencies, fibrinolytic disorders, homocystinuria, lupus anticoagulant, and factor XII deficiency. Clinical features that should raise suspicion of an inherited hypercoagulable state include a family history of thrombotic problems, recurrent thrombosis without precipitating factors, thrombosis at unusual locations or at an early age, and resistance to conventional antithrombotic therapy. Patients may also develop acquired hypercoagulable states secondary to a wide array of disease processes such as malignancy, pregnancy, estrogen use, disseminated intravascular coagulation, heparin-induced thrombocytopenia, myeloproliferative disorders, Cushing's disease, diabetes mellitus, and the nephrotic syndrome. Sites of Thrombosis. The autopsy studies of Sevitt and Callager'" demonstrated that thrombosis can begin at one or more independent sites in an injured or uninjured extremity. The six primary sites are listed in Table 2. Several conclusions may be drawn from these observations. The most common sites of thrombosis are the calf and iliofemoral veins. Calf vein thrombosis remains localized 800/0 of the time without proximal propagation. Superficial femoral thombi are usually secondary to extension of calf vein thrombi. Iliac and common femoral vein thrombosis can arise independently or may be part of a continuous thrombus lrom more distal sites. Sevitt and Gallager also reported that thrombosis occurred bilaterally in 42% of cases. Unilateral thrombosis most commonly occurred on the left side, presumably because of the obstructive effects of the right internal iliac artery on the left iliac vein. 73 Pulmonary Embolism The majority (>75%) of clinically significant pulmonary emboli arise from the proximal veins of the lower extremity and pelvis." 68 Thrombi in the calf veins are of smaller caliber, and embolization from this site alone would rarely be hemodynamically significant. With proximal propagation (as occurs in 15% to 20% of calf thrombi), the incidence of pulmonary embolism is 50%.77 Axillary and subclavian vein thromboses are additional sources of pulmonary emboli that have been increasingly recognized. A recent review demonstrated a 28% incidence of thrombosis associated with Table 2. Primary Site of Venous Thrombosis Intramuscular veins of the calf, especially the soleus Posterior tibial veins Popliteal vein near the adductor ring Deep femoral and superficial femoral vein junction Common femoral vein External iliac vein just above the inguinal ligament

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subclavian central lines and a 12% incidence of pulmonary embolism in those patients with upper-extremity deep venous thrombosis. 25 The physiologic effects of a pulmonary embolus are thought to be primarily mechanical and related to blockage of a pulmonary artery by the embolus, A secondary effect resulting from reflex bronchoconstriction and vasoconstriction, mediated by vasogenic amines arising from the embolism itself, also has been described.?' The effects of the embolus may include a ventilation-perfusion mismatch with systemic hypoxemia or pulmonary hypertension with cardiac failure. Survival depends on the size of the embolus and the underlying physiologic reserves. Even relatively small pulmonary emboli can be clinically significant in patients with severe cardiorespiratory insufficiency. Recognition of the multiple predisposing factors for thrombosis present in the vast majority of leu patients is critical to the prevention and treatment of this important clinical problem.

RISK FACTORS The incidence of deep venous thrombosis varies with the type of surgical procedure performed and the presence of clinical risk factors that predispose patients to thrombosis (Table 3). Following evaluation of surgical indications and the identification of risk factors, a patient may be classified as being at low, moderate, or high risk for the development of a thrombus, as described by Hull et al. 28 Low-risk patients are those under age 40 with no additional risk factors who undergo elective and uncomplicated minor abdominal or thoracic surgery with a general anesthesia time of less than 30 minutes. These patients have less than a 10% chance of developing a calf vein thrombosis, less than a 1% chance of proximal (popliteal or above) vein thrombosis, and a less than 0.01 % chance of suffering a fatal pulmonary embolism, Table 3. Risk Factors for Deep Venous Thrombosis History of deep venous thrombosis or pulmonary embolism Varicose veins Age greater than 40 Surgery longer than 30 minutes Paraplegia!quadriplegia Spine fractures without paraplegia Pelvic fractures Malignancy Obesity Prolonged immobilization (greater than 3 days' bedrest) Estrogen use Pregnancy Burns Hypercoagulable states Congestive heart failure

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Moderate-risk patients are over 40 years old, undergo general anesthesia for greater than 30 minutes, and also have one or more of the following: malignancy, obesity, varicose veins, paralysis, prolonged bedrest, or cardiac failure. The patients in the moderate-risk group who do not receive prophylaxis have a 10% to 40% risk of developing calf vein thrombosis, a 2% to 10% risk of proximal vein thrombosis, and a 0.1% to 0.7% risk of fatal pulmonary embolism. High-risk patients are those with a history of deep vein thrombosis or pulmonary embolism who require surgery. Additionally, victims of severe traumatic injuries, patients undergoing extensive abdominal or pelvic surgery for advanced malignancy, and patients requiring major orthopedic surgery to the lower extremities are classified in the high-risk group. Without prophylaxis, these patients have a 40% to 80% risk of calf vein thrombosis, a 10% to 20% risk of proximal vein thrombosis, and a 1% to 5% risk of fatal pulmonary embolism. The great majority of ICU patients can be classified in the high-risk category because of their comorbid disease processes and multiple risk factors. 56 This justifies an aggressive approach to the identification, prophylaxis, and treatment of deep venous thrombosis in critical care patients.

DIAGNOSIS Deep Venous Thrombosis: Clinical Diagnosis The clinical diagnosis of deep venous thrombosis is accurate in only about 50% of cases;"' 68 because the clinical findings are both insensitive and nonspecific. Sensitivity is low because many thrombi are nonocclusive and therefore clinically silent. Specificity is low because the symptoms and signs of deep venous thrombosis can also be caused by other disorders. 21 When clinical features are present, the most useful indicators are local tenderness, diffuse swelling of the extremity, pain or a sensation of heaviness in the extremity, and increased skin temperature. The frequently discussed Homans' sign (pain in the calf with passive dorsiflexion of the foot) is present in only about 10% of patients with documented deep venous thrombosis or pulmonary embolism. 75 The weakness of clinical indicators should not imply that the history and physical examination can be abandoned. The taking of a history and the performance of a careful physical examination are important, as resulting clinical suspicion may lead to early detection and treatment. Objective screening. and diagnostic tests are essential, because the majority of patients with deep venous thrombosis are asymptomatic. A fatal pulmonary embolism can occur even without clinical evidence of deep venous thrombosis. II High-risk ICU patients are frequently noncommunicative and may have multiple injuries or problems that mimic or mask the

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signs and symptoms of deep venous thrombosis and pulmonary embolism. Thus, for leu patients, diagnostic tests are indicated routinely to' rule out these conditions. Deep Venous Thrombosis: Diagnostic Tests

Venography. The venogram remains the gold standard with which all other diagnostic modalities are compared. Venography requires considerable experience to perform and interpret properly. The criteria for a positive examination should be strict. Only intraluminal filling defects or a vessel cut-off associated with collaterals and minimal proximal filling are considered positive signs.:" False-positive tests may result from streaming of the contrast medium, which then fails to opacify the entire vessel. Incomplete venous filling and other technical problems lead to inadequate studies in as many as 5% of patients. 60 The complications of venography include pain in the foot during the examination and pain in the calf 1 to 2 days later. There is also a wellestablished 1% to 2% incidence of new thrombosis secondary to endothelial cell injury caused by hypertonic contrast material. 36 Therefore, improvements in noninvasive methods for the detection of deep venous thrombosis have led to an increase in their use for both symptomatic and asymptomatic patients. lmpedence Plethysmography. Impedence plethysmography noninvasively measures changes in impedenee accompanying changes in blood volume of the lower extremity. A thigh blood pressure cuff is inflated and then deflated for this test. In normal persons, there is a progressive increase in blood volume in the calf after inflation of the thigh cuff followed by a rapid runoff after the cuff is deflated. In a positive examination, there is a venous outflow obstruction, and the run-off is delayed. This examination is easily obtained, is relatively inexpensive, and can be performed at the bedside. It has a 92% sensitivity and a 96% specificity for proximal thrombosis in the popliteal, femoral, and iliac veins when compared with venography. 35 Because impedence plethysmography measures impedence to outflow, false-positive tests can result from a more proximal cause of high venous pressure. These causes include right-sided heart failure, pelvic masses producing venous compression, and the presence of mechanical ventilation. Lower-extremity muscular contraction during the test or severe arterial vascular disease also produce falsely positive results. Impedence plethysmography is insensitive to thrombosis limited to the calf veins or to small, nonocclusive proximal thrombi. 26, 33 Serial impedence plethysmography evaluations combined with a 125 1 fibrinogen scan have been shown to be as accurate as venography for the diagnosis of deep venous thrombosis. In some cases, treatment decisions can be safely made on the basis of the results of these noninvasive examinations alone. 26, 32

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1251-Fibrinogen Scanning. The 125I-fibrinogen scan measures the incorporation of injected radiolabeled fibrinogen into an actively forming thrombus with an isotope detection camera." The test is considered positive if there are one or more areas of increased radioactivity (20%) after 48 hours when compared with identical areas of the other leg. 125I-Fibrinogen leg scanning detects more than 90% of acute calf vein thrombi but only 60% to 80% of proximal thrombi. It is insensitive to thrombi in the proximal thigh and pelvis because of background radiation from the trunk." In many cases, the length of time (24-72 hours) required for a positive result limits the usefulness of this test. 125I-fibrinogen leg scanning cannot be used in pregnant or lactating patients because the isotope crosses the placenta and is secreted in breast milk. There is also an increased number of false-positive tests if there are fractures, hematomas, surgical wounds, or an inflammatory process present in the lower extremity.21, 44, 75 Doppler Ultrasonography. Doppler ultrasonography involves directing an ultrasound beam at an underlying vein. Flowing blood directs the beam back at a changed frequency (the Doppler effect), which produces an audible signal. Normally, venous flow is phasic with breathing, and spontaneous sounds can be heard over a patent vein. In a patent venous system, augmentation of flow will occur when manual compression is applied distally. Valve function can also be assessed; in patent valves, there should be no reflux flow when compression is released. The Doppler examination alone has a diagnostic sensitivity of 76% to 96% and a specificity of 84% to 100% compared with venography;" An experienced examiner can determine patency in the common femoral, superficial femoral, and popliteal veins. Duplex Scanning. Combining B-mode with Doppler ultrasound is called duplex scanning. The B-mode ultrasound scan can visualize the vein longitudinally or transversely, depending on the orientation of the transducer. The imaged vein is compressed manually with the transducer. Normal veins are compressed and disappear, while veins containing thrombi are not compressed." 12, 45 The duplex scan has an overall sensitivity of 89% to 100% and a specificity of 97% to 100%.36 It is very useful for detecting deep venous thrombosis from the inguinal ligament to the popliteal vessels, but the duplex scan cannot evaluate veins in the pelvis or calf or the common iliac vessels.": 23, 36, 75, 76 The recent development of color-flow Doppler scanners may increase the accuracy of the duplex scan below the knee. 13 The duplex scan has its limitations. The equipment is expensive, and an experienced technologist is required to perform the scan for approximately 30 to 60 minutes to obtain accurate results. Deep Venous Thrombosis: Clinical Applications Noninvasive evaluations performed at the bedside are invaluable as methods of surveillance to detect asymptomatic deep venous thrombosis in

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ICU patients. 12 With the high accuracy of the current noninvasive diagnostic modalities, clinicians can institute treatment for most patients based solely on the results of these tests. When there is a contraindication to treatment, a venogram should be performed to confirm the diagnosis before a final therapeutic course is chosen. Serial examinations may be indicated despite an initial negative evaluation, with the aim of early identification and treatment of a new or asymptomatic proximal deep venous thrombosis. This is particularly true for patients who are in the ICU for long periods, during which time their risk remains high (Fig. 1). Pulmonary Embolism: Clinical Diagnosis The clinical diagnosis of pulmonary embolism is just as nonspecific as that of deep vein thrombosis. None of the symptoms or signs of pulmonary embolism is unique, and all can be mimicked by other cardiorespiratory diseases." More than 50% of patients clinically suspected of having pulmonary embolism have negative test results;" Clinical manifestations of a pulmonary embolism include dyspnea, chest pain, hemoptysis, altered mental state, tachycardia, tachypnea, rales, leg edema, increased central venous pressure, cyanosis, and hypotension. The clinical presentation can range from asymptomatic, if the pulmonary embolism is small and. the patient healthy, to sudden shock and cardiac arrest, if the embolus is large or the patient has an underlying cardiorespiratory insufficiency with little reserve.

TREATMENT Figure 1. Algorithm for the diagnosis of deep venous thrombosis in symptomatic or highrisk patients in the ICU. IPG = impedence plethysmography.

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Appropriate diagnostic laboratory tests include arterial blood gases, a chest radiograph, and an ECC. Blood gases may show hypoxemia but are nonspecific, and a normal p 0 2 does not rule out embolus." 21, 27 A chest radiograph is a mandatory part of the evaluation of a suspected pulmonary embolism, Despite its lack of diagnostic specificity, the chest film is needed to rule out other etiologies that mimic pulmonary embolism, as well as for the adequate interpretation of a ventilation-perfusion scan. The Westermark sign (a regional paucity of vascular markings) is unreliable for the diagnosis of a pulmonary embolism. The 12-lead ECC rarely demonstrates the classic finding of a pulmonary embolism (right axis deviation, 51, Q3, T3 pattern). The most frequent finding is that of 5T -segment depression secondary to myocardial ischemia from arterial hypotension and a decreased cardiac output. As with deep venous thrombosis, the clinical evaluation of pulmonary embolism is inadequate for the diagnosis, and objective diagnostic testing is required.

Pulmonary Embolism: Diagnostic Tests

Ventilation-Perfusion Lung Scan. Performance of a ventilation-perfusion lung scan (V/o. scan) is usually the first step in the screening for and diagnosis of a pulmonary embolism. The affected area of the lung is demonstrated by a mismatch of normal ventilation and a segmental or larger defect in perfusion. A chest radiograph should always be used for correlation with the Vio. scan images, as many pulmonary diseases (especially chronic obstructive pulmonary disease) and some cardiac conditions are accompanied by abnormalities in the distribution of pulmonary blood flow. The results of a ventilation-perfusion scan are commonly grouped into categories of high probability, intermediate probability, or low probability for a pulmonary embolism. A normal scan correlated with a normal chest film will rule out a pulmonary embolism. 50 A segmental or larger perfusion defect with a ventilation mismatch is considered a high-probability scan. This result has been shown to have a positive predictive value of 86% and, for most patients, provides sufficient evidence to justify the institution of therapy. 31 Intermediate- or low-probability scans demonstrating smaller subsegmental defects with or without mismatch must be considered inconclusive. Pulmonary emboli have been demonstrated angiographically in 20% to 40% of these patients. 30, 31 Thus, patients with intermediate- or lowprobability scans require further testing with pulmonary angiography to confirm the diagnosis. Pulmonary Angiography. Pulmonary angiography is the most accurate and reliable procedure for the diagnosis of pulmonary emboli. A large-bore catheter is placed in the pulmonary artery, followed by a high-pressure injection of contrast material. Contrast may be injected into the entire pulmonary vasculature, or a selective injection may be indicated by a previous abnormal Vio. scan. Pulmonary emboli appear as vascular cut-offs

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or intravascular filling defects. 44, 51 A well-performed pulmonary angiogram with negative results reliably excludes the diagnosis of pulmonary embolisln. 21 Indications for pulmonary angiography include an indeterminate VI¢. scan, a high-probability scan in a patient with a contraindication to heparin, suspected pulmonary embolism in patients with chronic obstructive pulmonary disease and inadequate VI¢. scans, a massive pulmonary embolism prior to embolectomy, and prior to placement of a vena cava filter. 44 A large review of pulmonary angiography complications reported an overall mortality rate of 0.2% and a complication rate of 4.5%.51 Most of the deaths occurred in high-risk patients with pulmonary hypertension and right ventricular dysfunction. The actual role of pulmonary angiography in causing death is unknown, but transient increases in pulmonary artery pressure secondary to ionic contrast material have been implicated.

Pulmonary Embolism: Clinical Application All patients with a clinically suspected pulmonary embolism should first have their lower extremities evaluated. If deep venous thrombosis is identified, treatment should be started. If the lower extremity evaluation is negative or inconclusive, or if treatment is contraindicated, specific evaluation for a pulmonary embolism is warranted before a final therapeutic decision is reached. A ventilation-perfusion scan should be done initially, and if a high-probability scan is demonstrated, treatment may be initiated on this basis. An intermediate- or low-probability scan mandates a pulmonary angiogram to confirm the diagnosis. The results of the intermediateor low-probability scan are valuable even if the scan is not diagnostic, as they may direct the angiographer to the affected side and allow for a selective right or left pulmonary angiogram with a smaller contrast load (Fig. 2). Pulmonary angiography is unobtainable in approximately 20% of patients because of severe hemodynamic instability. 30 In these difficult cases, a clinical decision is based on weighing the relative risks of treatment without diagnostic confirmation, confirming the diagnosis, or no treatment at all. A new technique for bedside pulmonary angiography has recently been described that may be especially useful in patients too ill to undergo standard angiography but for whom pulmonary embolectomy or lytic therapy is being considered;"

PREVENTION AND PROPHYLAXIS Seventy-five per cent of pulmonary emboli originate in the venous system of the lower extremity, 6, 68 and 80% of patients who suffer a fatal pulmonary embolism lack clinical signs of deep venous thrombosis or previous nonfatal pulmonary ernbolism.!' Ideally, therapy that prevents

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EVALUATE LOWER EXTREMITIES NONINVASI VE TESTS OR VENOGRAPHY

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Figure 2. Algorithm for the diagnosis of clinically suspected pulmonary embolism in symptomatic or high-risk patients in the ICU.

deep venous thrombosis should protect the patient from a fatal pulmonary embolism. The choice of prophylactic agent should be based on an individual patient's risk of deep venous thrombosis as well as on the efficacy and potential complications associated with each form of prophylaxis. Prophylactic agents fall into two general categories: mechanical or pharmacologic. Mechanical Prophylaxis

External Pneumatic Compression. Intermittent external pneumatic compression is a mechanical technique that increases venous emptying and augments pulsatile venous flow, preventing venous stasis. It also induces both local and systemic fibrinolysis through currently unknown mechanisms.:" In patients with one lower extremity unavailable because of casts, dressings, or external fixators, the device can be placed on the uninvolved lower extremity and still retain the potentially beneficial fibrinolytic effect. Many clinical trials have shown a decreased incidence of deep venous thrombosis from an average 22.9% in controls to 6. 7% in treated patients. 62 There are no reported complications or side effects of external compression.

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Inferior Vena Cava Procedures. Surgical methods of preventing a lower-extremity deep venous thrombus from embolizing to the pulmonary circulation have evolved from ligation of the femoral vein or inferior vena cava to applying partially occluding clips externally to the inferior vena cava.:" Percutaneous devices designed for this purpose have been available for 10 to 15 years. The widely used Greenfield filter is a six-pronged cone placed via the femoral or jugular vein and positioned just inferior to the renal veins. The geometric shape of the cone allows emboli to collect at the apex while maintaining flow around the periphery, permitting embolic filling of approximately 80% of the cone before flow is decreased. Patency rates are greater than 98% with this device, and recurrent emboli occur in less than 4% of cases. 17 Currently accepted indications for placement of the Greenfield filter include: (1) recurrent pulmonary embolus despite adequate anticoagulation; (2) deep venous thrombosis with a contraindication to anticoagulation (e.g., recent major trauma, particularly head trauma, and neurosurgery); (3) complications while the patient is anticoagulated; (4) as a prophylactic measure in patients at high risk for recurrent pulmonary emboli (iliofemoral thrombus with a floating tail); (5) after a massive pulmonary embolus where a recurrent embolus would be fatal; and (6) after a pulmonary embolectomy. 1, 5,15 Pharmacologic Prophylaxis

Low-Dose Heparin. In 1950, de Takats observed that less heparin was required to prevent clotting than to treat an already established clot and suggested prophylaxis using small doses of subcutaneous hcparin.!" Small doses of heparin have subsequently been shown to prevent thrombosis by accelerating the rate of inhibition of coagulation by antithrombin III. The reason that a much smaller dose of heparin is needed to prevent coagulation than to treat established venous thrombosis stems from the fact that only a small quantity of coagulation factors need to be inhibited to prevent initiation of the coagulation cascade. However, once the coagulation cascade has been initiated, the activation process is amplified in each successive step, and a much larger dose is required to stop it. 28 The usual prophylactic dose is 5000 units subcutaneously 2 hours prior to surgery followed by 5000 units subcutaneously every 8 or 12 hours in the postoperative period. Monitoring of anticoagulation is not necessary. A review of more than 70 randomized trials of 16,000 patients in general, orthopedic, and urologic surgery demonstrated that perioperative subcutaneous heparin prevents approximately 68% of all deep vein thrombosis and 50% of all pulmonary emboli. 8 The number of deaths from pulmonary embolism is also reduced with low-dose heparin." Minor bleeding at the injection site and wound hematoma have been reported. They occur with slightly increased frequency on an 8-hour dosage schedule; however, there is no apparent increase in risk for major hemorrhagic complications at either dose interval. 38, 49

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Adjusted-Dose Heparin. The adjusted-dose heparin regime was developed for patients undergoing a total hip replacement. Two days prior to surgery, the patient is started on 3500 units of subcutaneous heparin every 8 hours, and the dose is adjusted according to the activated partial thromboplastin time (APTT). The goal is to maintain the APTT in the highnormal range (31.5-36 seconds). A study of patients having total hip replacement demonstrated reduction of the incidence of deep venous thrombosis from 39% to 13%.47 Warfarin. Warfarin blocks the synthesis of vitamin K-dependent clotting factors II (prothrombin), VII, IX, and X in the liver. The dosage required for prophylaxis is adjusted to maintain the prothrombin time in the low therapeutic range. The disadvantages in using warfarin for routine prophylaxis are the 5% to 10% incidence of major hemorrhage and the increased time required for achievement of adequate anticoagulation. 38, 49 The prophylactic use of warfarin is limited to elective surgical procedures with a very high risk of deep venous thrombosis, such as total hip replacement. In this setting, the incidence of deep venous thrombosis can be reduced approximately 66%, and that of pulmonary embolism reduced 80%, compared with controls. 38 Prophylaxis: Clinical Applications With the myriad possible illnesses encountered in the leu and the high frequency of multiple life-threatening disease processes in the same patient, deep venous thrombosis prophylaxis must be individualized. External compression devices have the lowest complication rates and are easily applied in almost all patients. Used alone, they are the prophylactic measure of choice in neurosurgery and spine surgery patients because of the hemorrhagic risks of anticoagulant prophylaxis. External compression devices and low-dose heparin may be used as single agents or in combination for moderate- or high-risk general and thoracic surgery patients. Isolated acute orthopedic injuries require adjusted-dose heparin or low-dose warfarin for adequate prophylaxis, and an external compression device on the uninvolved extremity is also beneficial. The multiple-trauma patient poses special problems. The risk of hemorrhage from the prophylaxis must be balanced against the risk of deep venous thrombosis with inadequate prophylaxis. The external compression device is the most commonly used modality and can be applied in most patients. If there is a low risk of hemorrhage, low-dose subcutaneous heparin or low-dose warfarin may be added. For patients with a contraindication to anticoagulation and unable to wear compression devices who are at high risk for pulmonary embolism (i.e., pelvic fractures or bilateral lower-extremity fractures), a percutaneously placed Greenfield filter should be considered as prophylaxis against pulmonary embolism. 69, 70 In addition to the prophylactic measures, a baseline noninvasive examination of the lower extremities should be performed to exclude the

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presence of deep venous thrombosis prior to the institution of prophylaxis. The bedside study should be repeated at regular intervals to allow for early detection of an asymptomatic proximal extension or the development of a new deep venous thrombosis. 2, 12

DEFINITIVE TREATMENT Deep Venous Thrombosis Many randomized trials have demonstrated that patients with proximal deep venous thrombosis require anticoagulation to prevent recurrent venous thrombosis and potential pulmonary embolism. 29, 34 Thrombolytic agents or surgical therapy are also needed occasionally. There is some disagreement regarding whether calf deep venous thrombosis mandates anticoagulation. In general, the risk of proximal extension and possible pulmonary embolization must be weighed against the risks associated with anticoagulation. A recent review demonstrated that asymptomatic isolated calf thrombus rarely embolizes without prior proximal propagation, and no fatal pulmonary emboli were reported in patients presenting with isolated calf thrombi. 58 This finding would suggest that therapeutic anticoagulation may be withheld and these patients followed by serial noninvasive tests. 58, 65 If the patient becomes symptomatic or the noninvasive tests demonstrate proximal propagation, treatment should be started.:" If accurate serial noninvasive testing cannot be performed, and in patients for whom even a small pulmonary embolism would be lifethreatening, treatment should begin as soon as even a calf deep venous thrombosis is diagnosed. Anticoagulant Therapy. Heparin is the primary pharmacologic agent for the definitive treatment of acute deep venous thrombosis. The anticoagulant effect of heparin occurs on several levels. First, heparin combines with the naturally occurring inhibitor antithrombin III and potentiates its inhibition of the activated coagulation factors IIa, IXa, Xa, XIa, and XIIa. At higher doses, heparin enhances the inhibitory effect of the naturally occurring heparin cofactor lIon thrombin, and it may also have an inhibitory effect on platelet function. The anticoagulant effect of heparin is immediate, and heparin has a half-life of 60 minutes. 59 The dose of heparin required for systemic anticoagulation is variable. The usual therapeutic dose is a 5,000- to 10,000-unit bolus followed by a constant infusion of approximately 30,000 to 40,000 units/day. The dosage must be adequate to prolong the APTT to a therapeutic range of 1.5 times control or to reach therapeutic heparin levels of 0.3 to 0.5 units/ml. Failure to achieve adequate anticoagulation, especially in the first 24 hours, has been shown to carry a 25% risk of recurrent deep venous thrombosis versus a risk of 2% if the APTT is 1.5 times control. 34 The heparin should be given by continuous infusion and

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the dose adjusted according to the APTI' or heparin level. Heparin requirements are usually higher during the first few days of therapy, and as such, monitoring should be frequent. Once an adequate dose is determined, the APTI' or heparin level can safely be checked once a day. The phenomenon of "heparin resistance" is present when the patient's APTI' does not increase despite high heparin dosages (>50,000 units/24 hoursl.:" Heparin resistance is often only a laboratory finding. These patients may have had an abnormally low APTI' prior to treatment because of high levels of circulating procoagulants. Many such patients have a heparin level that is within the therapeutic range. True heparin resistance occurs when both the APTI' and the heparin levels remain subtherapeutic despite large doses of heparin. This is seen in the early stages of therapy and is usually secondary to increased heparin clearance. Heparin resistance secondary to low antithrombin III levels is rare. Low levels of antithrombin III influence the APTT if below 25% of normal. Patients with a congenital antithrombin III deficiency usually respond to heparin. The most common complication of heparin therapy is bleeding, occurring in approximately 5% to 10% of patients. 59 The greatest risk is associated with the higher total dosages of heparin during the first 5 days of treatment. Most bleeding complications are minor; however, major hemorrhage can occur, and the retroperitoneum is an important site of bleeding that may remain occult. 24 Thrombocytopenia secondary to a heparin-induced platelet antibody is seen in 5% to 6% of patients receiving heparin 71 and is manifested by falling platelet counts and arterial or venous thrombosis resulting from platelet aggregation. Platelet counts should be followed in all patients receiving heparin, and, if the count falls to less than 100, 000/mm 3 , this diagnosis should be entertained. Cessation of all heparin is both a diagnostic and a therapeutic maneuver for thrombocytopenia. The duration of heparin therapy is generally 7 to 10 days, as this is the time required for the stabilization and adherence of the thrombus to the vessel wall. 52 The patient is then switched to warfarin. If warfarin is contraindicated, adjusted-dose subcutaneous heparin should be used. 59 Warfarin, an orally administered anticoagulant with a half-life of 42 hours, produces a decrease in the vitamin K-dependent clotting factors prothrombin (II), VII, IX, and X. It also decreases the levels of the naturally occurring anticoagulants protein C and protein S. When initiating therapy, it must be recognized that factor VII and protein C have the shortest halflives and are depleted first. Despite the fact that the prothrombin time may be prolonged shortly after the initiation of therapy, a relative hypercoagulable state may develop because of the depletion of protein C. The full anticoagulant effect is not seen until factors II, IX, and X are also depleted. Heparin and warfarin therapy should overlap for a few days to protect against this potential hypercoagulable state. 37, 56, 74 After 4 to 5 days of continuous intravenous heparin, the patient is

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started on warfarin sodium, overlapping administration of heparin and warfarin until the prothrombin time has been therapeutic for at least 2 days. The therapeutic goal is a prothrombin time that is 1.3 to 1.5 times the control value. An initial dose schedule of 5 mg/day will usually achieve the therapeutic range in 36 to 48 hours, although some adjustments may be necessary. A loading dose is not recommended, as it does not change the speed of anticoagulation and may result in a potentially dangerous overdose. Patients who may be unusually sensitive to warfarin include the elderly or malnourished and those with hepatic dysfunction, fever, heart failure, or hyperthyrotdtsm. In addition, drug interactions must be considered, as warfarin is highly protein bound, and drugs that displace warfarin from albumin (such as aspirin and nonsteroidal anti-inflammatory agents) will increase its bioavailability and action. 74 Therapy should be continued for 3 to 6 months. In patients with recurrent thrombosis or other risk factors, longer periods of treatment are indicated. 36, 38, 52 Although it is contraindicated in pregnant patients because of multiple reports of fetal abnormalities, warfarin can be used in nursing mothers, as it is not excreted in breast milk. 57, 74 As with heparin, bleeding is the major complication. Minor bleeding occurs in 4.8% of patients, and major bleeding necessitating cessation of therapy or transfusions occurs in 2%.57 Warfarin-induced necrosis (thought to be related to the decreased protein C levels at the initiation of therapy) occurs most commonly in the breasts, buttocks, abdomen, and thighs. 41 The necrosis can involve the skin, adipose tissue, and even underlying muscle. Treatment for necrosis is cessation of warfarin, the institution of heparin, and aggressive wound care. Thrombolytic Therapy. Thrombolytic therapy is generally reserved for those patients suffering extensive proximal deep venous thrombosis with limb-threatening ischemia. Thrombolytic therapy accelerates the lysis of venous thromboemboli but also increases the incidence of bleeding complications. The most commonly used thrombolytic agents are streptokinase, urokinase, and, most recently, tissue plasminogen activator. In the absence of contraindications, thrombolytic therapy should be started immediately, as a 2- to 3-day delay decreases the chances of successful lysis by 50%.53 Whether thrombolytic therapy is efficacious in reducing the frequency of postphlebitic sequelae of deep venous thrombosis or the mortality rate of pulmonary embolism is still unknown. The majority of leu patients are not candidates for treatment with these agents because of the potential for bleeding. 53

Surgical Therapy. Thrombectomy of an iliofemoral thrombosis will rarely be needed. The best results are seen in young, healthy patients with ischemic extremities secondary to extensive proximal thrombosis for whom thrornbolvtir. therapy has failed or is contraindicated. To be effective, the procedure should be performed within 48 hours of the development of the thrombus, before fibroblast ingrowth attaches it to the vessel wall. 16, 22, 63

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Anticoagulant Therapy. A randomized trial in 1960 and several since have demonstrated improved survival rates in patients treated with anticoagulation." 20 Bolus heparin followed by a constant infusion with subsequent conversion ·to warfarin sodium is standard. The dosage regimes are similar to those used in deep venous thrombosis. However, in patients with a massive pulmonary embolus, larger doses of heparin are required initially to achieve an adequate anticoagulant effect because of accelerated heparin clearance. Thrombolytic Therapy. Thrombolytic therapy accelerates the lysis of pulmonary emboli, but the clinical advantage over routine anticoagulation has never been definitively demonstrated. At present, its use is reserved for patients with a massive hemodynamically significant pulmonary embolus who have no contraindications.:" Surgical Therapy. Surgical therapy has been used to treat massive acute pulmonary embolism and also in the treatment of pulmonary hypertension associated with chronic thrombotic occlusions of the pulmonary arteries. In the acute situation, an embolectomy can be performed by an open technique requiring cardiopulmonary bypass or by a closed technique using catheters. Surgery is employed as a last resort in critically ill patients who have failed all other forms of therapy, as the mortality rate is high. 14, 39 For most patients with a sublethal pulmonary embolism, the embolism resolves and, barring recurrent emboli, does not involve longterm consequences. A small subgroup of patients develop pulmonary hypertension secondary to chronic thrombotic obstruction of major pulmonary arteries. In these patients, a pulmonary thromboendarterectomy may result in a substantial improvement and is associated with an acceptable morbidity and mortality rate. 54

SUMMARY

The ICU patient population is at a high risk for the development of deep venous thrombosis leading to a potentially fatal pulmonary embolism. It is vital to appreciate this risk and apply appropriate prophylaxis. Constant vigilance is required, as deep venous thrombosis and pulmonary emboli can develop and progress despite standard prophylactic measures. In unstable patients, more aggressive prophylaxis may be warranted, including the use of inferior vena cava filters. A high index of suspicion and a low threshold for screening and diagnostic testing will allow earlier recognition and treatment of this lifethreatening condition. Treatment decisions are based on clinical suspicion, diagnostic examination results, and the potential complications of difficult treatment modalities.

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David B. Hoyt, MD Division of Trauma UCSD Medical Center H-640-B 225 Dickinson Street San Diego, CA 92103