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CHAPTER 56: Venous Thromboembolism Including Pulmonary Embolism 389 Venous Thromboembolism Including Pulmonary Embolism Jeffrey A. Kline INTRODUCTION AND EPIDEMIOLOGY Pulmonary embolism (PE) occurs when clotted blood enters the pulmonary arterial circulation. Most PEs result from deep vein thrombosis (DVT) in the legs, arms, or pelvis and occasionally from the jugular vein or inferior vena cava. The term venous thromboembolism (VTE) includes PE and DVT. In the United States, approximately 200,000 people will have new or recurrent PE diagnosed each year, and twice that many will have DVT without confirmed PE. 1 About 1 in 500 children (age <18 years) are tested for VTE in EDs, with about 10% being diagnosed with VTE; the rate of diagnosis in children is rising, perhaps as a result of longer survival of children with chronic complex comorbidity and increased use of estrogen-containing oral contraceptives. 2-4 VTE incidence varies slightly with geography across the United States but varies widely among hospitals. 5 EDs with older, sicker patients diagnose more VTE cases. The incidence of VTE increases with age, peaking at 1 in 100 per year at age 80. Based on autopsy data, PE is the second leading cause of sudden, unexpected, nontraumatic death in outpatients. 6 The case fatality rate from PE depends on the hemo dynamic severity of the PE, age, and comorbid conditions; the case fatality rate is 45% for PE with circulatory shock, but only about 4% to 5% of patients with PE have shock. In patients with hemodynamically stable PE who are less than 50 years old and without other comorbidi ties, the case fatality rate is 1%. Morbidity from PE includes the post-PE syndrome, which occurs in about 25% of patients after PE and is characterized by chronic fatigue, dyspnea, exercise intolerance, and low perception of health status. An extreme form of post-PE syndrome, occurring in about 3% of PE patients, is chronic thromboembolic pulmonary hypertension, which causes disabling dyspnea. 9 Morbidity from DVT includes PE and the postthrombotic syndrome, with the latter manifested as chronic leg swelling and pain; it occurs in about 20% of all ED patients with proxi mal DV T. 10 Both PE and DVT have a spectrum of severity, with minor forms of the disease including distal PE (called subsegmental) and distal DVT (usually in the calf or saphenous veins). PATHOPHYSIOLOGY Blood clots occur when coagulation exceeds the removal by fibrinolysis. Thrombophilias are conditions that tip the balance of coagulationfibrinolysis toward excessive clotting. Most guidelines categorize VTE as provoked or unprovoked (also called idiopathic). 12 Provoked VTEs are a consequence of a triggering risk factor for clots, such as recent surgery, trauma, or any condition associated with limb or body immo bility; active cancer can be a persistent provoking factor for VTE. Other provoking factors generally include diseases or conditions that impede venous blood flow, infection, chronic disease, estrogen use, pregnancy or initial postpartum interval, and age >50 years (each year after 50 increases the risk). Most VTEs diagnosed in the ED are unprovoked. 7,13 Patients with unprovoked VTE have a 15% chance of recurrence in the next year compared with 5% for those with a provoked episode. Those with provoked VTE have a higher 1-year death rate, likely from the comorbid condi tions (notably cancer).

ter 50 increases the risk). Most VTEs diagnosed in the ED are unprovoked. 7,13 Patients with unprovoked VTE have a 15% chance of recurrence in the next year compared with 5% for those with a provoked episode. Those with provoked VTE have a higher 1-year death rate, likely from the comorbid condi tions (notably cancer). Venous thrombi that are large enough to cause clinically important PE can form in the popliteal, common femoral, superficial femoral, pelvic, axillary, jugular, and great veins. At least one third of patients with DVT have concomitant PE, even when the patient lacks symptoms of PE. 15 Although 75% to 80% of hospitalized patients with PE have image-demonstrated DVT, only 40% of ambulatory ED patients with PE have concomitant DVT. Patients without prior heart or lung disease generally begin to experience symptoms from PE with at least 20% of lung vasculature occluded.17 With larger clot burden, the pulmonary arterial pressure increases, leading to right ventricular dilation and myocardial damage, causing the release of troponin and B-type natriuretic peptide. Right ventricular dilation or injury, detected by an increased right ventricular to left ven tricular ratio on CT scan or echocardiography; right ventricular strain suggested by elevated troponin or B-type natriuretic peptide; or signs of an acute pulmonary hypertension on 12-lead ECG indicate right heart failure and increased risk of circulatory shock and death. 18-20 Patients with PE generally die from one of the following two mechanisms: 1. Abrupt near-total pulmonary artery occlusion that leads to pulseless electrical activity or asystole from ischemic effect on the His-Purkinje conduction system. 2. Progressive right heart failure and circulatory shock, which occurs over hours to days. Blood clots in the femoral and iliofemoral veins usually form on the valves, leading to scarring and poor function of the venous valves. This causes venous reflux and pooling of venous blood in the legs, leading to varicose veins, pain, swelling, skin hyperpigmentation, and ulcers, known as the postthrombotic syndrome. Inherited thrombophilias increase risk of first-time VTE, although most of these patients are unaware of this condition until a clot occurs. The risk of recurrent VTE in those with a known thrombophilia is the same as patients with unprovoked VTE and no known thrombophilia. With limb immobility, VTE risk increases depending on joint, as follows: elbow (least), shoulder, ankle, knee, and hip (most). Acute immobilization of the hip and knee in one leg with non–weight bearing causes the greatest risk for VTE, whereas immobilization of the wrist alone probably causes no added risk. In addition to the presence of limb immobility, risk of VTE increases with whole-body immobility or neu rologic immobility and with travel >8 hours. Over half of patients with postoperative PE are diagnosed after hos pital discharge, and the average time from surgery to PE diagnosis is >10 days. Risk increases with patient age, longer surgery, open surgery, and surgery absent thromboprophylaxis. The highest-risk surgical pro cedures include abdominal surgery to remove cancer, joint replacement surgery, and surgery on the brain or spinal cord in the setting of neu rologic deficits. The 4-year risk of postsurgical acquired PE recurrence ranges from 5% to 11% per year depending on the procedure. Thrombogenic potential of cancer varies with host factors, tumor stage, and tumor type. In general, the risk of VTE increases with the more undifferentiated the cell type and the larger the tumor burden (especially distant metastasis). Adenocarcinoma (pancreatic, ovar ian, and colon), glioblastoma, metastatic melanoma, lymphoma, and multiple myeloma are particularly thrombogenic.

or stage, and tumor type. In general, the risk of VTE increases with the more undifferentiated the cell type and the larger the tumor burden (especially distant metastasis). Adenocarcinoma (pancreatic, ovar ian, and colon), glioblastoma, metastatic melanoma, lymphoma, and multiple myeloma are particularly thrombogenic. 24 Cancers with lower risk of VTE include localized breast, cervical, prostate, and non melanomatous localized skin cancers such as squamous cell carcinoma and basal cell carcinoma not treated with chemotherapy. In general, patients with cancer are at their highest risk of developing VTE during chemotherapy. A family history of VTE increases longitudinal risk of VTE 25 and may increase risk of VTE diagnosis in symptomatic ED patients. 13,26 Although sex does not significantly modify the risk of first-time VTE, men have more recurrent VTE. Table 56-1 presents a list of risk factors for VTE relevant to ED practice. Although smoking causes conditions that increase risk (e.g., cancer) and acts synergistically with obesity and possibly oral contraceptive use, smoking alone does not increase the risk of VTE diagnosis in symptomatic ED patients. Patients with missed PE who are admitted to the hospital for other reasons tend to have a higher frequency of altered mental status (either new or existing) and preexisting heart and lung disease. 28-31 One study examined patients discharged with PE and found they were more likely to not have dyspnea, but instead to have isolated pleuritic chest pain CHAPTER Tintinalli_Sec07_p0329-0424.indd 389 8/2/19 6:42 PM

gher frequency of altered mental status (either new or existing) and preexisting heart and lung disease. 28-31 One study examined patients discharged with PE and found they were more likely to not have dyspnea, but instead to have isolated pleuritic chest pain CHAPTER Tintinalli_Sec07_p0329-0424.indd 389 8/2/19 6:42 PM 390 SECTION 7: Cardiovascular Disease and hemoptysis together with a pulmonary infiltrate on imaging and a lower d-dimer concentration with a small distal clot seen on pulmonary vascular imaging.30 CLINICAL FEATURES OF PULMONARY EMBOLISM PE symptoms range from none to sudden death. Patients with similar comorbidities and clot burden may have drastically different clinical presentations. Table 56-2 lists factors that affect symptoms. The hallmark of PE is dyspnea unexplained by auscultatory findings, ECG changes, and without a clear alternative diagnosis on chest radiograph. Chest pain with pleuritic features is the second most common symptom of PE, although about one half of all patients diagnosed with PE in the ED have no chest pain. 7 The classic PE pain is in the thorax between the clavicles and the costal margin that increases with cough or breathing; it is not substernal and emanating from the skin or muscle. Pulmonary infarction (lung tissue destruction) can inflict severe focal pain, usually occurring 1 to 3 days after the embolic event. infarction in basilar lung segments can refer pain to either shoulder, or it can mimic biliary or ureteral colic. Proximal PE without infarction can also cause pleuritic chest pain without focal pain.  HISTORY In addition to the common symptoms of chest pain and dyspnea, approximately 3% to 4% of ED patients with PE have syncope, and another 1% to 2% present with new-onset “seizure” (or convulsionlike activity) or confusion. 3 Because about 20% of people have a patent foramen ovale, PE that increases right-sided pressures can lead to rightto-left transit of thrombotic material in the atria and showers into the brain circulation, producing stroke-like symptoms called the paradoxical embolism syndrome. Neurologic symptoms can vary widely, from classic localized findings to staring spells, transient altered mental status, and atypical myelopathy symptoms (e.g., numbness in an extremity or below the waist), all of which can fluctuate. 33 Presence of a patent fora men ovale worsens the prognosis in PE.  PHYSICAL EXAMINATION On physical examination, abnormal vital signs suggest acute cardiopul monary stress in a patient with PE; these include tachycardia, tachypnea, a lowered pulse oximetry reading, and sometimes mild fever. Unfortu nately, PE does not predictably alter any vital sign; approximately one half of patients with proven PE have a heart rate of <100 beats/min at diagnosis, and approximately one third have abnormal early vital signs that normalize in the ED. 34 The mechanism of altered vital signs results in obstruction to blood flow and clot-derived autacoids, which together stimulate adrenergic efferent fibers to the heart and cause ventilation–perfusion mismatch on the lungs. The amount of clot burden does not predict vital sign changes reliably, with no clear correlation between measured clot and initial heart rate or oximetry. Fever neither increases nor decreases the probability of PE diagnosis in symptomatic ED patients. The physical examination, aside from vital signs, is most likely to be helpful through two findings: 1. Unilateral limb swelling (with or without an indwelling catheter), which increases probability of PE diagnosis by three-fold 2. Wheezing, which reduces probability of PE by one half Most patients with PE have clear lungs on auscultation.

ion, aside from vital signs, is most likely to be helpful through two findings: 1. Unilateral limb swelling (with or without an indwelling catheter), which increases probability of PE diagnosis by three-fold 2. Wheezing, which reduces probability of PE by one half Most patients with PE have clear lungs on auscultation. Wheezes or bilateral rales make an alternative diagnosis of bronchospasm or TABLE 56-1 Risk Factors for Venous Thromboembolism (VTE) That Are Generally Relevant to Emergency Medicine Factor Comment Age Risk becomes significant at 50 y and increases with each year of life until age 80 y. Obesity In the general population, VTE risk starts at BMI >35 kg/m and increases with increasing BMI. Pregnancy and postpartum state PEs can occur in any trimester and postpartum. Prior VTE Highest risk of recurrence is for unprovoked VTE in men, particularly if d-dimer remains elevated. Solid cancers Risk greatest with adenocarcinomas and metastatic disease. A history of remote, inactive cancer probably does not increase risk. Hematologic cancers Acute leukemias and myeloma confer the greatest risk, particu larly when treated with l-asparaginase and the thalidomide derivatives. Thrombophilias Non-O blood type, lupus anticoagulant, shortened aPTT, factor V Leiden, and familial protein C and S and antithrombin defi ciency have the strongest risk. Recent surgery or major trauma Risk increased with endotracheal intubation or epidural anesthesia and continues at least 4 weeks after exposure. Risk varies with type of surgery. Immobility Acute limb immobility of two contiguous joints confers the highest risk. Bed rest Becomes a risk factor at approximately 72 h. Indwelling catheters Cause approximately one half of arm deep venous thromboses. Long-distance travel Published data are controversial. In general, risk becomes significant after 6 h of continuous travel. Smoking A population risk factor, but not a factor that increases probability of VTE in the ED setting. May increase risk of other factors such as obesity. Congestive heart failure Related primarily to severity of systolic dysfunction. Stroke Risk greatest in first month after deficit. Estrogen Highest-risk period is in the first few months. All contraceptives containing estrogen increase risk of VTE including transdermal and transvaginal preparations. Noninfectious inflammatory conditions Examples are inflammatory bowel disease, lupus, and nephrotic syndrome. Risk of VTE increases roughly in propor tion to severity of underlying disease. Abbreviations: aPTT = activated partial thromboplastin time; BMI = body mass index; PE = pulmonary embolism. TABLE 56-2 Factors That Can Affect the Clinical Presentation of Patients With Pulmonary Embolism (PE) Cofactor Clinical Impact Comment Previously healthy and young age Less severe signs and symptoms One half of previously healthy patients with first-time PE have normal vital sign values at diagnosis. Prior cardiopulmonary disease Can either amplify or obscure history and findings Most patients with PE complicating baseline cardiopulmonary disease describe dyspnea with PE as “worse than usual.” Patient cognitive dysfunction Causes the history to be less reliable Approximately 20% of patients with PE missed by ED clinicians had baseline dementia. Clot size and location Affects severity of dyspnea, pain, and signs Proximal clots cause ventilation– perfusion mismatch and dyspnea; distal clots cause infarction with pain. Gradual loading of PE over time Gradual onset of dyspnea on exertion and fatigue Has symptom overlap with left ventricular dysfunction. Fewer than one half of patients with PE describe symptom onset as sudden. Tintinalli_Sec07_p0329-0424.indd 390 8/2/19 6:42 PM

atch and dyspnea; distal clots cause infarction with pain. Gradual loading of PE over time Gradual onset of dyspnea on exertion and fatigue Has symptom overlap with left ventricular dysfunction. Fewer than one half of patients with PE describe symptom onset as sudden. Tintinalli_Sec07_p0329-0424.indd 390 8/2/19 6:42 PM CHAPTER 56: Venous Thromboembolism Including Pulmonary Embolism 391 pneumonia possible but do not completely exclude PE; pulmonary infarction may produce rales over the affected lung segment. The over all gestalt interpretation of “sick/not sick” appearance of ED patients with possible PE can be deceiving; one study found that patients diagnosed with PE were more likely to smile during their physical examination.  PULSE OXIMETRY, CHEST RADIOGRAPH, AND ECG Pulse oximetry, chest radiograph, and ECG obtained in the ED generally demonstrate nonspecific findings in patients with PE. The mean pulse oximetry reading is lower in patients with proven PE than in those without PE; while lowered room air oxygen saturation is common, a pulse oximetry reading of 100% does not reliably exclude PE. Spontaneously breathing patients with PE also demonstrate a lower end-tidal carbon dioxide compared with healthy individuals. Most patients with PE have a chest radiograph with one or more abnormalities, including cardiomegaly, basilar atelectasis, infiltrate, or pleural effusion; all are nonspecific for PE. In <5% of patients, a wedgeshaped area of lung oligemia (called Westermark’s sign—usually from complete lobar artery obstruction) or peripheral dome-shaped dense opacification (Hampton’s hump—indicative of pulmonary infarction) exists. The presence of hypoxemia or dyspnea with clear lungs on physical exam and chest radiography suggests the need to test for PE. Findings of acute pulmonary hypertension on ECG increase the probability of PE. These findings are not typically recognized by computer interpretations and include a heart rate >100 beats/min, T-wave inver sion in leads V 1 to V 4, incomplete or complete right bundle branch block, and the S 1-Q3-T3 pattern ( Figure 56-1).37 A clinical ECG score also allows severity assessment in those with diagnosed PE (higher score equates to higher mortality, Table 56-3; See Video: ECG: Pulmonary Embolism). 38,39 CLINICAL FEATURES OF DEEP VEIN THROMBOSIS Patients with DVT complain of extremity pain, swelling, or cramping. A difference of ≥2 cm between right and left leg diameter at 10 cm below the tibial tubercle doubles the likelihood of DVT. Patients presenting with upper extremity catheter-related DVT often complain of hand swelling or tightness around finger rings. About one quarter of patients with DVT have tenderness and redness in the swollen extremity, find ings that are like those of cellulitis. Calf or saphenous vein clots are more likely to cause thrombophlebitis, defined formally as inflammation (pain, tenderness, redness, and swelling) over a vein secondary to the presence of thrombotic material in the vein. Signs and symptoms of thrombo phlebitis can persist after the venous recannulation and after the clot has dissolved entirely. Calf vein thrombosis may cause Homan’s sign, which is calf pain that occurs with passive foot dorsiflexion; this test has such low sensitivity and specificity that it has no predictive value. Proximal DVT that causes complete venous obstruction can create elevated compartmental pressures, manifested as an extremely painful, FIGURE 56-1. This 12-lead ECG shows many features of a severe pulmonary embolism: tachycardia, an incomplete right bundle branch block, an S 1-Q3-T3 pattern, and T-wave inversion in the anterior leads. [Image contributed by Department of Emergency Medicine, Wake Forest Baptist Hospital.] Tintinalli_Sec07_p0329-0424.indd 391 8/2/19 6:42 PM

-lead ECG shows many features of a severe pulmonary embolism: tachycardia, an incomplete right bundle branch block, an S 1-Q3-T3 pattern, and T-wave inversion in the anterior leads. [Image contributed by Department of Emergency Medicine, Wake Forest Baptist Hospital.] Tintinalli_Sec07_p0329-0424.indd 391 8/2/19 6:42 PM 392 SECTION 7: Cardiovascular Disease TABLE 56-3 ECG Scoring Method to Assess Severity of Pulmonary Embolism 39 Characteristics Score Tachycardia (>100 beats/min) 2 Incomplete right bundle branch block 2 Complete right bundle branch block 3 T-wave inversion in leads V1 through V4 4 T-wave inversion in lead V1 * <1 mm 0 1–2 mm 1 >2 mm 2 T-wave inversion in lead V2 * <1 mm 1 1–2 mm 2 >2 mm 3 T-wave inversion in lead V3 * <1 mm 1 1–2 mm 2 >2 mm 3 S wave in lead 1 0 Q wave in lead 3 1 Inverted T wave in lead 3 1 If all S1-Q3-T3 pattern, add 2 Total score (maximum: 21) *If present, check maximum only. swollen extremity. Phlegmasia alba dolens is a swollen, painful, and pale or white limb with a proximal venous thrombosis, whereas a limb with a dusky or blue color is phlegmasia cerulea dolens. Either condition poses the threat of limb loss, demanding aggressive treatment that can include clot disruption.  DIAGNOSTIC TESTING FOR VENOUS THROMBOEMBOLISM DECISION RULES AND CLINICAL ASSESSMENT Estimating the pretest probability for VTE in a patient is the first step in selecting a diagnostic pathway. Figure 56-2 shows the author’s diagnostic algorithm; no singular diagnostic test or algorithm perfectly excludes or diagnoses VTE. Aggressive diagnostic searches can cause harm from hemorrhage caused by anticoagulation for a false-positive result or self-limited small clot diagnosis or from toxicity related to testing itself, such as contrast allergies, kidney injury, or cancer risk. One approach is to test further only in those with pretest probabilities of >2.5% 40; those with a pretest probability of PE of <2.5% are more likely to be harmed—either directly or by responding to a test result with more testing or care—than helped by a diagnostic test, including a simple d-dimer assay. The PE rule-out criteria ( Table 56-4) reliably forecast a probability of PE that is below the 2.0% test threshold in patients with a gestalt low clinical suspicion. 41-43 The American College of Emergency Physicians, the American College of Physicians, and the American Society of Hematology current guidelines all recommend use of the PE rule-out criteria rule, 44-46 which has been validated in multiple groups. 41,47 The weight of the available information indicates that PE can be reliably excluded by the combination of a low gestalt pretest probability plus a negative PE rule-out criteria rule. However, not all patients with any positive PE rule-out criteria must undergo an objective test for PE, since anyone over 50 years old would be tested with any finding even if suspicion was low. The key is generating a clinical gestalt first ; if low, then use the PE rule-out criteria to guide testing. Other PE and DVT prediction tools exist. The Wells’ original rules separate patients into low-, moderate-, and high-probability groups for PE and DVT, with a stepwise increase in probability of clot presence with higher scores (Tables 56-5 and 56-6) . The newer modified Wells’ scoring system classifies patients into a low-risk (score ≤4) or a non– low-risk group (score >4) 48 and has become popular.49 The Wells’ rule has a subjective component—clinical judgment of the likelihood of an alternative diagnosis. Both the Charlotte and the simplified, revised Geneva score ( Table 56-7 ) exclude subjective assessments.

fies patients into a low-risk (score ≤4) or a non– low-risk group (score >4) 48 and has become popular.49 The Wells’ rule has a subjective component—clinical judgment of the likelihood of an alternative diagnosis. Both the Charlotte and the simplified, revised Geneva score ( Table 56-7 ) exclude subjective assessments. Unstructured gestalt pretest probability, divided into low (<15%), moderate (15% to 40%), and high (>40%) categories, is an alternative and valid method to estimate pretest probability; ultimately, well-done estimation using any tool or gestalt is better than none. d-DIMER TESTING The d-dimer assay is the only useful blood test to exclude VTE, work ing on the principle that clots contain fibrin that is degraded naturally through the action of plasmin. d-Dimer levels are reported either as fibrinogen equivalent units in nanograms per milliliter or d-dimer units in nanograms per milliliter. In general, 1 d-dimer unit equals 2 fibrino gen equivalent units. Different d-dimer assays have different thresholds for normal, which can generate confusion, but in general, emergency physicians are advised to use the locally recommended threshold. For PE and DVT, the diagnostic sensitivity of automated quantitative d-dimer assays ranges from 94% to 98%, and the specificity ranges from 50% to 60%. 46,52 The d-dimer has a half-life of approximately 8 hours and can be elevated for at least 3 days after symptomatic VTE. The most common causes of a false-negative or false-positive d-dimer result are listed in Table 56-8; notably, all risk factors for VTE may elevate the d-dimer level. d-Dimer increases with age; the accept able normal threshold is adjusted upward for age to increase exclusion ary ability in older patients. 53 The most common formula studied is age×10 nanograms/mL (e.g., an 80-year-old patient would have an adjusted threshold for abnormal at 800 nanograms/mL). 49 This assumes the conventional d -dimer cutoff of 500 nanograms/mL; in a large multicenter study, this adjusted approach resulted in a very low falsenegative rate (0.3%) when used in conjunction with a Wells’ score ≤4 or a simplified revised Geneva score <5. 49 The YEARS study reported that patients with a low pretest probability and a d-dimer concentration that is twice the usual cutoff value (e.g., at 1000 ng/mL instead of 500 ng/mL) have a <1% probability of PE. IMAGING  CHEST CT ANGIOGRAPHY Chest CT angiography is the most common imaging modality for PE, identifying a clot as a filling defect in contrast-enhanced pulmonary arteries (Figure 56-3). The diagnostic sensitivity and specificity of a technically adequate multidetector CT pulmonary angiography scan are both approximately 90%. The sensitivity of CT is not adequate to exclude PE in patients with a high pretest probability. 55 Most CT pulmonary angiography protocols require the patient to lie supine and hold their breath for a few seconds, and the scan requires injection of approximately 120 mL of contrast by a computer-controlled injection device. The patient must have a peripheral IV catheter (20 gauge or larger) or an approved indwelling line to allow injection of the contrast, and a central catheter cannot be used for injection. In addition to clot recognition, a CT scan can detect alternative diagnoses, often pneumonia (8% to 22% of cases). 56 Interobserver agreement in identifying segmental or larger filling defects is very good, but interobserver agreement for subsegmental clots is poor. In practice, approximately 10% of CT scans are inadequate from secondary motion artifact or poor pulmonary artery opacification, commonly in obese or very tachypneic patients. About 15% of patients undergoing contrastenhanced chest CT scan develop mild contrast nephropathy.

ver agreement for subsegmental clots is poor. In practice, approximately 10% of CT scans are inadequate from secondary motion artifact or poor pulmonary artery opacification, commonly in obese or very tachypneic patients. About 15% of patients undergoing contrastenhanced chest CT scan develop mild contrast nephropathy. 57,58 At present, no clearly helpful prophylactic measure exists to reduce Tintinalli_Sec07_p0329-0424.indd 392 8/2/19 6:42 PM CHAPTER 56: Venous Thromboembolism Including Pulmonary Embolism 393 Does patient have a sign or symptom of pulmonary embolism? Is your clinical suspicion for PE low? Gestalt <15% or Wells’ score <2 Neither PERC rule PE+ Bilat LE CUS Homogenous perfusion (normal) Diagnostic + Nondiagnostic Quantitative D-dimer* Order imaging Serum Cr→ GFR <60 mL/min V/Q planar or V/Q SPECT CTPA Serum Cr→ GFR >59 mL/min Consider LMWH if no contraindication Yes PE unlikely: Wells 2–4 or sRGS 2–4 Yes PE likely: High (gestalt >40%) Wells >4 sRGS >4 +− + + − − <500 FEU nanograms/mL or < age × 10 nanograms/mL ≥500 FEU nanograms/mL or ≥ age × 10 nanograms/mL FIGURE 56-2. Proposed algorithm for evaluation of suspected pulmonary embolism. Begin with the pulmonary embolism rule-out criteria (PERC) rule—diagnostic  algorithm for pulmonary embolism (PE). *Some physicians prefer to start with a clinical decision rule such as the Wells’ score (where <2, 2–6, and >6 are used instead of <15%, 15% to 40%, and >40%, respectively). Note: Determine renal function by clinical picture (healthy, no risk factors for reduced glomerular filtration rate [GFR]) or calculated GFR. Nondiagnostic ventilation–perfusion (V. /Q. ) scan findings require confirmation from results of another test, such as CT pulmonary angiography (CTPA), if benefits outweigh risks. + = positive for PE; – = negative for PE; Bilat LE CUS = bilateral lower extremity compression US; Cr = creatinine; FEU = fibrinogen equivalent units; High = high-probability scan findings; LMWH = low-molecular-weight heparin; Nondiagnostic = any reading other than normal or high probability; quant = quantitative; SPECT = single-photon emission CT; sRGS = simplified, revised Geneva score; V. /Q. = ventilation/perfusion ratio. Tintinalli_Sec07_p0329-0424.indd 393 8/2/19 6:42 PM

h-probability scan findings; LMWH = low-molecular-weight heparin; Nondiagnostic = any reading other than normal or high probability; quant = quantitative; SPECT = single-photon emission CT; sRGS = simplified, revised Geneva score; V. /Q. = ventilation/perfusion ratio. Tintinalli_Sec07_p0329-0424.indd 393 8/2/19 6:42 PM 394 SECTION 7: Cardiovascular Disease TABLE 56-4 Pulmonary Embolism Rule-Out Criteria Rule (all nine factors must be present to exclude pulmonary embolism)41 •   Clinical low probability (<15% probability of pulmonary embolism based on gestalt assessment) •  Age  <50 years •  Pulse  <100 beats/min during entire stay in ED •   Pulse oximetry >94% at near sea level (>92% at altitudes near 5000 feet above sea level) •  No  hemoptysis •  No  prior venous thromboembolism history •   No surgery or trauma requiring endotracheal or epidural anesthesia within the last 4 wk •  No  estrogen use •   No unilateral leg swelling, defined as asymmetrical calves on visual inspection with patient’s heels raised off the bed TABLE 56-5 Original Wells’ Score for Pulmonary Embolism Factor Points* Suspected deep venous thrombosis 3 Alternative diagnosis less likely than PE Heart rate >100 beats/min 1.5 Prior venous thromboembolism 1.5 Surgery or immobilization within prior 4 wk 1.5 Active malignancy 1 Hemoptysis 1 *Risk score interpretation (probability of pulmonary embolism): >6 points = high risk (78.4%); 2–6 points = moderate risk (27.8%); and <2 points = low risk (3.4%). Source: Adapted with permission from Wells PS, Anderson DR, Rodger M, et al: Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the model utility with the SimpliRED d-dimer. Thromb Haemost 2000 Mar;83(3):416-420. Figure 3, Pg 418. TABLE 56-6 Wells’ Score for Deep Vein Thrombosis (DVT) Clinical Feature Points* Active cancer (treatment within 6 mo, or palliation) 1 Paralysis, paresis, or immobilization of lower extremity 1 Bedridden for >3 d because of surgery (within 12 wk) 1 Localized tenderness along distribution of deep veins 1 Entire leg swollen 1 Unilateral calf swelling of >3 cm (10 cm below tibial tuberosity) Unilateral pitting edema 1 Collateral superficial veins 1 Alternative diagnosis as likely as or more likely than DVT –2 Prior history of DVT or pulmonary embolism † 1 *Risk score interpretation (probability of DVT) in original Wells DVT model: ≥3 points = high risk (75%); 1 or 2 points = moderate risk (17%); <1 point = low risk (3%). †Only awarded in the modified (dichotomized) Wells DVT model: ≤1 point = DVT unlikely; >1 point = DVT likely. Source: Adapted from Geersing GJ, Zuithoff NP, Kearon C, et al: Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ 348: g1340, 2014. TABLE 56-7 Revised and Simplified, Revised Geneva Score (RGS) for Pulmonary Embolism50 Points Clinical Variable RGS* Simplified RGS† Age >65 y 1 1 Previous venous thromboembolism 3 1 Surgery requiring anesthesia or fracture of lower limb in past month 2 1 Active malignancy 2 1 Unilateral leg pain 3 1 Hemoptysis 2 1 Pain on lower limb deep vein palpation with unilateral leg edema 4 1 Heart rate 75–94 beats/min 3 1 >95 beats/min 5 1 *Total score of 0–3 indicates low probability, score of 4–10 indicates moderate probability, and score of >10 indicates high probability of pulmonary embolism. †Score ≤4 indicates that pulmonary embolism is unlikely.

limb deep vein palpation with unilateral leg edema 4 1 Heart rate 75–94 beats/min 3 1 >95 beats/min 5 1 *Total score of 0–3 indicates low probability, score of 4–10 indicates moderate probability, and score of >10 indicates high probability of pulmonary embolism. †Score ≤4 indicates that pulmonary embolism is unlikely. TABLE 56-8 Factors Known to Alter the d-Dimer Level From Expected Values Potential False-Positive Levels Potential False-Negative Levels Age >70 y Symptoms lasting >5 d Pregnancy Presence of small clots Active malignancy or metastasis Isolated small pulmonary infarction Surgical procedure in previous week Isolated calf vein thrombosis Liver disease Lipemia Rheumatoid arthritis Infections Trauma FIGURE 56-3. Axial image from a chest CT angiogram demonstrating a filling defect consistent with acute pulmonary embolism. Two white arrowheads outline a circular filling defect in the right middle lobar pulmonary artery. The long white arrow projecting in the left lung points to a filling defect in a segmental artery in the posterior medial segmental artery. Tintinalli_Sec07_p0329-0424.indd 394 8/2/19 6:42 PM

ith acute pulmonary embolism. Two white arrowheads outline a circular filling defect in the right middle lobar pulmonary artery. The long white arrow projecting in the left lung points to a filling defect in a segmental artery in the posterior medial segmental artery. Tintinalli_Sec07_p0329-0424.indd 394 8/2/19 6:42 PM CHAPTER 56: Venous Thromboembolism Including Pulmonary Embolism 395 contrast nephropathy, including hydration with IV balanced crystal loid solutions .59-61 Other CT angiogram complications include anaphylactoid reactions (<1:1000), contrast extravasation into a limb that can cause pain or compartment syndrome, and creation of a secondary thrombophlebitis.  PLANAR VENTILATION–PERFUSION LUNG SCANNING Ventilation–perfusion (V. /Q. ) lung scanning can identify a perfusion defect when ventilation is normal. The perfusion images are usually obtained first and require a peripheral IV catheter for injection; the patient must be able to sit up and then lie down during the procedure. The ventilation component requires the patient to breathe a nebulized aerosol with isotope. A V/Q  scan with homogeneous scintillation throughout the lung in the perfusion portion is nearly 100% sensitive in excluding PE, regardless of the appearance of the ventilation portion. V/Q  scan with two or more apex central wedge-shaped defects in the perfusion phase (Figure 56-4A) with normal ventilation in these regions indicates >80% probability of PE. All other V/Q  scan findings are nondiagnostic; taken alone, these cannot exclude or diagnose PE. The V/Q  single-photon emission CT technique produces threedimensional images with better diagnostic accuracy and lower interob server variability than planar V/Q  .63 The pooled diagnostic accuracy of V/Q  single-photon emission CT is extraordinarily good; a 2015 systematic review and meta-analysis of 3454 patients found a pooled sensitivity of 96% (95% confidence interval [CI], 95% to 97%) and a specificity of 97% (95% CI, 96% to 98%). V/Q  single-photon emission CT detects subsegmental perfusion defects. 63 Single-photon emission CT can also be combined with low radiation dose CT scanning to produce colormapped images that can be even more revealing (Figure 56-4B).  MAGNETIC RESONANCE IMAGING MRI is a zero-radiation option for imaging the pulmonary vasculature that may have utility in pregnant patients. However, pooled data suggest that the diagnostic accuracy of MRI for all examinations, regardless of technical adequacy of images, is too low (sensitivity of 75% with speci ficity of 80%) to consider as a first-line modality.  LUNG US Lung US is an adjunctive modality to help diagnose and exclude PE at the bedside. One study found an improvement in the diagnostic accu racy of the Wells’ score when using lung US to determine the presence or absence of an alternative diagnosis. 65 Pooled data suggest that lung US has a sensitivity of 85% (95% CI, 78% to 90%) and specificity of 83% (95% CI, 73% to 90%).  VENOUS US Venous US is the imaging test of choice in DVT; it can be done quickly, does not use ionizing radiation, and provides direct evidence of intravascular thrombus by observing noncompressibility of the vein (Figure 56-5). When performed by experienced ultrasonographers, compression venous US has a diagnostic sensitivity of 96% and a speci ficity of 96% for DVT; it also has a sensitivity of about 40% as a surrogate method to diagnose PE. The mean sensitivity for DVT of US performed by a trained emergency physician compared with the reference imaging test is 96.1% (95% CI, 90.6% to 98.5%), with a weighted mean specificity of 96.8% (95% CI, 94.6% to 98.1%). 67 However, the details of test performance and training remain important, because two-point compression FIGURE 56-4. A.

or DVT of US performed by a trained emergency physician compared with the reference imaging test is 96.1% (95% CI, 90.6% to 98.5%), with a weighted mean specificity of 96.8% (95% CI, 94.6% to 98.1%). 67 However, the details of test performance and training remain important, because two-point compression FIGURE 56-4. A. Planar ventilation–perfusion lung scan series consistent with a high probability of acute pulmonary embolism (PE) using standard criteria. The first and third rows project the perfusion phases of the examination, and the second and fourth rows show the ventilation phases. The black arrowheads point to wedge-shaped defects in the perfusion images. Comparison with the corresponding ventilation view immediately below shows relatively homogeneous scintillation activity in the anatomic segments that lack perfusion. These defects are consistent with an acute PE. B. Ventilation and perfusion single-photon emission CT (SPECT) images from a patient with PE. The red arrows point to the perfusion defects indicative of PE. The lower panel shows the color-mapped images produced by SPECT/CT; the segments of lung without blood flow appear black. [Part B: This research was originally published in JNM. Roach PJ, Schembri GP and Bailey DL. V. /Q. scanning using SPECT and SPECT/CT. J Nucl Med. 2013;54(9):1588-1596. Figure 4. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.] Tintinalli_Sec07_p0329-0424.indd 395 8/2/19 6:42 PM

lood flow appear black. [Part B: This research was originally published in JNM. Roach PJ, Schembri GP and Bailey DL. V. /Q. scanning using SPECT and SPECT/CT. J Nucl Med. 2013;54(9):1588-1596. Figure 4. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.] Tintinalli_Sec07_p0329-0424.indd 395 8/2/19 6:42 PM 396 SECTION 7: Cardiovascular Disease FIGURE 56-5. Compression venous US images showing normal findings and findings indicating deep venous thrombosis. A. Compression venous US of the common femoral vein and femoral artery. The left view shows a sonographic image of the right femoral artery (A) and common femoral vein (V) obtained immediately inferior to the inguinal ligament. The image on the right shows the same view after manual compression by the operator. The image demonstrates obliteration of the vein while the artery remains open. This is a normal US finding for the vein. B. Venous US image showing evidence of common left femoral vein thrombosis after compression (right panel). The common femoral vein (V) does not compress. Echogenic thrombolytic material can be observed within the vein. US may miss some clots and new users require experience with at least 10 examinations before gaining adequate skill. Planar pulmonary angiography and venography directly visualize filling defects in the pulmonary arteries or extremity veins, respectively. However, neither test is currently used as a first-line diagnostic modality.  INTEGRATED APPROACH TO DIAGNOSIS AND TREATMENT STEP ONE For a patient to enter a PE testing regimen, he or she should have at least one physiologic manifestation of PE . This may be a symptom (e.g., pain in the chest or torso, a breathing problem, or altered mental status) or a finding (e.g., an abnormal vital sign) that could be produced by a clot in the lung. The physiologic manifestation must be placed in the context of the given patient—an untreated asthmatic patient with shortness of breath and wheezing should be treated first for broncho spasm and reevaluated and not immediately tested for PE. A risk factor or even multiple risk factors for VTE in the absence of a known sign or symptom or a positive PE rule-out criteria rule with a <2% gestalt pretest probability of PE does not mandate testing for PE or DVT. STEP TWO After finding a physiologic manifestation of PE, the next step is to ask, “Do I have more than a low initial suspicion for PE?” Low suspicion means that the physician’s gestalt interpretation of the overall clinical picture is PE likelihood of <15%. If the answer to this question is yes, then a diagnostic test is needed. If the answer is no, then it remains possible that PE can be excluded using the PE rule-out criteria rule. If all eight criteria of the PE rule-out criteria rule are met in the setting of a gestalt-based low suspicion, then no further testing is necessary. In general, if any one of the eight criteria is not met or if a prominent finding exists, order a diagnostic test for PE. STEP THREE If PE cannot be excluded with the PE rule-out criteria rule, choose a diagnostic test result that can produce a posttest probability of <2.0%. An age-adjusted quantitative d-dimer assay is the best diagnostic test in patients for whom clinical suspicion is low or moderate based on either gestalt estimation, a Wells’ or simplified revised Geneva score of ≤4, or a “safe” designation according to the PE rule-out criteria rule. Patients with a low pretest probability (e.g., a reasonable alternative diagnosis to PE, no hemoptysis, and no signs of DVT) can have PE excluded with a d-dimer at twice the usual threshold ( Table 56-9). 46,52 STEP FOUR Test further only those with a positive d-dimer result or a high pretest probability; base the choice of the next test on patient and facility fac tors.

onable alternative diagnosis to PE, no hemoptysis, and no signs of DVT) can have PE excluded with a d-dimer at twice the usual threshold ( Table 56-9). 46,52 STEP FOUR Test further only those with a positive d-dimer result or a high pretest probability; base the choice of the next test on patient and facility fac tors. The algorithm presented in Figure 56-2 is one path. In general, the next best step for a patient with suspected PE and a positive d-dimer result is chest CT angiography. V/Q  scan may be a preferred option in a TABLE 56-9 Likelihood Ratios (LRs) of Diagnostic Tests and Pretest Probabilities Required to Diagnose or Exclude Pulmonary Embolism (PE) Test LR for PE if Test Result Is Negative LR for PE if Test Result Is Positive * Examples of Scores on Published Methods That Would Allow Pretest Probability to Rule Out VTE if Test Result Is Negative Qualitative d-dimer 0.25 2 Wells’ score <2, all pulmonary embolism rule-out criteria negative Quantitative d-dimer† 0.1 2 Gestalt estimate low, Wells’ score ≤4, or Charlotte rule negative (“safe”) Age adjustment of the d-dimer cutoff using the formula age × 10 nanograms/mL CT angiography 0.12 12 Gestalt estimate low, Wells’ score ≤4, or Charlotte rule negative (“safe”) . /Q. scan: normal 0.05 NA Any V. /Q. scan: high probability NA 12 NA Abbreviations: FEU = fibrinogen equivalent units; NA = not applicable; V . /Q . = ventilation–perfusion; VTE = venous thromboembolism. *A positive d-dimer result should not be used to rule in VTE. †Assumes a U.S. Food and Drug Administration–cleared assay with cutoff of 500 FEU nanograms/mL as threshold. Tintinalli_Sec07_p0329-0424.indd 396 8/2/19 6:42 PM

alent units; NA = not applicable; V . /Q . = ventilation–perfusion; VTE = venous thromboembolism. *A positive d-dimer result should not be used to rule in VTE. †Assumes a U.S. Food and Drug Administration–cleared assay with cutoff of 500 FEU nanograms/mL as threshold. Tintinalli_Sec07_p0329-0424.indd 396 8/2/19 6:42 PM CHAPTER 56: Venous Thromboembolism Including Pulmonary Embolism 397 –+– + Determine pretest probability of DVT using Wells’ criteria∗ Low probability score (<1 point) High or moderate probability score (>0 points) D-dimer testing D-dimer testing DVT ruled out Treat DVT DVT ruled out –+ –+ DVT ruled out Repeat US in 1 week ∗Wells PS, Anderson DR, Rodger M, et al: Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: increasing the model utility with the SimpliRED D-dimer. Thromb Haemost 83: 416-20, 2000. FIGURE 56-6. Diagnostic algorithm for deep vein thrombosis (DVT), applied in patients with leg symptoms compatible with DVT. + = positive test result; – = negative test result. 109 pregnant patient or in a patient with renal insufficiency or prior adverse reaction to contrast material. Performing lower extremity venous US is another option; it lacks ionizing radiation, and its ability to diagnose DVT in a patient with PE symptoms is tantamount to diagnosing PE directly. However, the diagnostic sensitivity of lower extremity US for PE is <40%, so all patients suspected of having PE for whom US findings are negative require pulmonary vascular imaging. A good-quality CT scan (adequately opacified vessels to the segmental artery level) or a normal V/Q  scan excludes PE. Anticoagulation should be started for all patients with a segmental or larger filling defect consistent with PE seen on CT scan, a high probability V/Q  scan, or a DVT seen on US. If the patient has no image-detected DVT or PE and has an elevated d-dimer concentration, then further imaging before anticoagulation is an option, especially if the patient has any increased risk of bleeding complications. Commonly, a repeat venous US within 2 to 7 days is an alternative option to exclude VTE. Figure 56-6 is one algorithm describing the diagnostic decision making for DVT. Patients with a low pretest probability (score <1) or patients without cancer, with a modified Wells’ DVT score ≤1 (Table 56-6), and with a normal d-dimer result are safely considered negative for DVT; any positive result requires US in this group. Patients with moderate to high Wells’ scores or DVT likely (modified Wells’ DVT score) should undergo US testing, assessing d-dimer as additional confirmation at physician discretion only if the US result is negative. In these patients, assume no clot exists if both US and d-dimer tests are negative; if patients have negative US findings and positive d-dimer results, repeat the US 2 to 7 days later.  VENOUS THROMBOEMBOLISM TREATMENT TREATMENT OF PULMONARY EMBOLISM AND DEEP AND SUPERFICIAL EXTREMITY THROMBOSES Treatment of VTE requires systemic anticoagulation to prevent further clot formation and allow endogenous fibrinolysis to proceed. In many cases, the initial treatment for VTE is heparin or a heparin-like drug. Patients with DVT diagnosed in the ED are typically discharged after TABLE 56-10 Antithrombotic Therapy for Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Therapy Dosage Comments Unfractionated heparin 80 units/kg bolus, then 18 units/kg/h infusion Recommended if outpatient therapy not appropriate or in cases of severe renal failure LMWH   Outpatient treatment with LMWH preferred Dalteparin 100 IU/kg SC every 12 h or 200 IU/kg SC every day

VT) and Pulmonary Embolism (PE) Therapy Dosage Comments Unfractionated heparin 80 units/kg bolus, then 18 units/kg/h infusion Recommended if outpatient therapy not appropriate or in cases of severe renal failure LMWH   Outpatient treatment with LMWH preferred Dalteparin 100 IU/kg SC every 12 h or 200 IU/kg SC every day Enoxaparin 1 milligram/kg SC every 12 h or 1.5 milligrams/kg SC every day

VT) and Pulmonary Embolism (PE) Therapy Dosage Comments Unfractionated heparin 80 units/kg bolus, then 18 units/kg/h infusion Recommended if outpatient therapy not appropriate or in cases of severe renal failure LMWH   Outpatient treatment with LMWH preferred Dalteparin 100 IU/kg SC every 12 h or 200 IU/kg SC every day Enoxaparin 1 milligram/kg SC every 12 h or 1.5 milligrams/kg SC every day Tinzaparin 175 IU/kg SC every day Factor Xa inhibitors Fondaparinux <50 kg, 5 milligrams SC every day; 50–100 kg, 7.5 milligrams SC every day; >100 kg, 10 milligrams SC every day Do not use in renal failure Target-specific anticoagulants Rivaroxaban (Xarelto®) 15 milligrams BID for 21 d, then 20 milligrams every day with food No heparin requirement; good choice for outpatient treatment Apixaban (Eliquis®) 10 milligrams BID for 7 days, then 5 mg BID No heparin requirement; good choice for outpatient treatment Dabigatran (Pradaxa®) 150 milligrams BID Requires run-in of heparin for 5–10 d; renal excretion Thrombolytic therapy Tissue plasminogen activator or alteplase (Activase®), 10-milligram IV bolus followed by 90 milligrams infused over 2 h For PE with hemodynamic compromise; after infusion, begin unfractionated heparin or LMWH Abbreviations: BID = twice a day; LMWH = low-molecular-weight heparin. receiving the first dose of low-molecular-weight heparin, apixaban, or rivaroxaban (Table 56-10), with anticoagulation continued as an outpatient. Indications for admission in patients with DVT are primarily dependent upon social determinants, comorbid conditions, and the presence of iliofemoral DVT with signs of phlegmasia. The two most common options are unfractionated heparin or a low-molecular-weight heparin (Table 56-10). 12 Initial anticoagulation treatment for VTE can also include oral apixaban or rivaroxaban. 12 For detailed discussion of antithrombotic therapy, see Chapter 239, “Thrombotics and Antithrombotics. ” Current data favor the use of low-molecular-weight heparins over unfractionated heparin for treatment of both PE and DVT in terms of composite outcomes (bleeding and death) and cost, although the magnitude of benefit is not large. 6 If uncertain about PE presence, the likelihood can guide anticoagulation therapy; the benefit of empiric anticoagulation for 24 hours exceeds the risks (bleeding and heparininduced thrombocytopenia) for any patient with a pretest probability of PE of >20%. 68 Delay in administration of heparin to patients with PE is associated with increased mortality, but no study has found that heparin, administered early and prior to imaging, improves morbidity or mortality. In patients with severe renal insufficiency and acute DVT or PE, most experts recommend unfractionated heparin over low-molecular-weight heparin. 12 Treat upper extremity DVT the same as lower extremity DVT, and consider removing any indwelling catheters associated with clot. Do not delay unfractionated heparin for thrombophilia testing.69 Most DVT can be treated with anticoagulation, but iliofemoral DVT that causes phlegmasia cerulea dolens requires rapid action to Tintinalli_Sec07_p0329-0424.indd 397 8/2/19 6:42 PM

DVT, and consider removing any indwelling catheters associated with clot. Do not delay unfractionated heparin for thrombophilia testing.69 Most DVT can be treated with anticoagulation, but iliofemoral DVT that causes phlegmasia cerulea dolens requires rapid action to Tintinalli_Sec07_p0329-0424.indd 397 8/2/19 6:42 PM 398 SECTION 7: Cardiovascular Disease reduce the venous pressure. In addition to initiating anticoagulation, place the affected limb at a neutral level; remove constrictive clothing, cast, or dressing; and arrange for vascular consultation and consultantdelivered catheter-directed thrombolysis. 70 If no such service is available and emergency transfer cannot be arranged within 6 hours, consider systemic fibrinolytics if there are no absolute contraindications. One regimen for the latter is 50 to 100 milligrams of alteplase infused IV over 4 hours. TREATMENT FOR SUPERFICIAL THROMBOPHLEBITIS Treatment for localized superficial thrombophlebitis is an oral NSAID or topical diclofenac gel until symptoms resolve; there is no need for systemic anticoagulation. For extensive superficial vein involvement, full-dose anticoagulation is recommended. 6 Compression stockings may provide some relief in selected individuals.71 TREATMENT FOR ISOLATED CALF VEIN THROMBOSIS There are no universally accepted treatment guidelines for throm boses isolated to the calf veins (soleal or gastrocnemius) or the saphenous vein, although many use 3 months of oral anticoagulation. 72 Alternatives include no acute treatment, with repeat US in 1 week to identify progression of clot, or outpatient treatment with low-molecularweight heparin (Table 56-10). Patients with a history of VTE or risk factors for VTE (Table 56-1) should receive 3 months of full-dose anti coagulation when calf thrombosis exists unless contraindications are present. OUTPATIENT TREATMENT OF PULMONARY EMBOLISM For carefully selected low-risk patients with PE, many centers have begun ED treatment protocols with a first dose of low-molecular-weight heparin, apixaban, or rivaroxaban given in the ED (Table 56-10), fol lowed by a period of ED observation, and then ED discharge with anticoagulation continued as an outpatient, as long as patients are able to obtain the drug and adhere to therapy. Patients with PE and a low risk of death plus adequate home sup port can qualify for outpatient anticoagulation. 73,74 The incidence of short-term mortality and the bleeding risk are very low with outpatient treatment, the overall cost of care is less, and the experience is preferred by patients. 75,76 Select low-risk patients using either the modified Hestia criteria or the Simplified PE Severity Index criteria ( Table 56-11).18,77,78 If low risk, assess the patient’s wishes and ability to comply; if no highrisk features exist (elevated troponin, a B-type natriuretic peptide >100 picograms/mL, pulmonary arterial hypertension on ECG, or bleeding risks 79), outpatient care after an ED stay (up to 23 hours) is an option; otherwise, short-term hospitalization is a good choice. FIBRINOLYSIS FOR PULMONARY EMBOLISM PE is classified into three categories based on severity: massive, submassive, and less severe PE. Massive PE patients have a systolic blood pressure of <90 mm Hg for >15 minutes, a systolic blood pressure of <100 mm Hg with a history of hypertension, or a >40% reduction in baseline systolic blood pressure. Submassive PE patients have normal or nearnormal blood pressure, but with other evidence of cardiopulmonary stress (Table 56-12). All other PE cases are “less severe. ” Patients with low-risk PE should not receive fibrinolysis; those with massive PE (defined as a systolic blood pressure <90 mm Hg or an observed decrease of 40 mm Hg) benefit from fibrinolysis.

rnormal blood pressure, but with other evidence of cardiopulmonary stress (Table 56-12). All other PE cases are “less severe. ” Patients with low-risk PE should not receive fibrinolysis; those with massive PE (defined as a systolic blood pressure <90 mm Hg or an observed decrease of 40 mm Hg) benefit from fibrinolysis. Patients with more severe submassive PE (i.e., causing increased right ventricular to left ventricular ratio on CT scan or hypokinesis, elevated troponin or B-type natriuretic peptide, or persistent hypoxemia with distress) may also benefit from fibrinolysis, including higher survival and better quality of life, although at a higher bleeding risk.  SYSTEMIC FIBRINOLYSIS The best evidence suggests considering systemic fibrinolysis in patients with no contraindications to fibrinolysis and any of the following: cardiac arrest; hypotension (any systolic blood pressure >90 mm Hg); respiratory failure, evidenced by severe hypoxemia (pulse oximetry reading <90%) despite oxygen administration, together with evidence of increased work of breathing; or evidence of right-sided heart strain on echocardiography or elevated levels of troponin T or I, or TABLE 56-11 Two Prognostic Systems That Can Select Low-Risk Patients for Outpatient Treatment18,73,74 Simplified PE Severity Index Score •  0  = low risk; 1 = high risk •  Age  >80 y •  History  of cancer •  History  of heart failure or chronic lung disease •  Pulse  >110 beats/min •  SBP  <100 mm Hg •  Oxygen  saturation <90% Modified Hestia Criteria •  Identifies  low-risk PE if: •  SBP  >100 mm Hg •  No  thrombolysis needed •  No  active bleeding •  Oxygen  saturation >94% on room air •  Not  already anticoagulated •  No  more than two doses of IV narcotics in ED •  Absence  of other medical or social reasons to admit •  Creatinine  clearance >30 mL/min •  Not  pregnant, no severe liver disease or HIT Abbreviations: HIT = heparin-induced thrombocytopenia; PE = pulmonary embolism; SBP = systolic blood pressure. TABLE 56-12 Modalities to Risk-Stratify Pulmonary Embolism (PE) Test Less Severe PE More Severe PE (massive and some submassive PE) Hestia criteria All negative Any positive PE Severity Index score <80 >120 Simplified PE Severity Index criteria All negative Any positive Shock index (heart rate/ systolic blood pressure) <1.0 ≥1.0 Pulse oximetry reading >94% <95% Echocardiography Normal RV systolic function Normal RV size No tricuspid regurgitation RV hypokinesis RV dilation RVSP >40 mm Hg Troponin I or T level Normal Elevated B-type natriuretic peptide level <90 picograms/mL ≥90 picograms/mL N-terminal pro-B-type natriuretic peptide <900 picograms/mL ≥900 picograms/mL d-Dimer level <4000 nanograms/mL >8000 nanograms/mL Serum sodium concentration <125 mEq/L ≥125 mEq/L Abbreviations: RV = right ventricular; RVSP = right ventricular systolic pressure. Tintinalli_Sec07_p0329-0424.indd 398 8/2/19 6:42 PM