PULMONARY EMBOLISM Background Pulmonary embolism (PE) is a common and potentially lethal condition that can cause death in all age groups. A good clinician should consider the diagnosis if any suspicion of pulmonary embolism exists, because prompt diagnosis and treatment can dramatically reduce the morbidity and mortality of the disease. Unfortunately, the diagnosis is often missed, because pulmonary embolism frequently causes only vague and nonspecific symptoms. The most sobering lessons about pulmonary embolism (PE) are those obtained from a careful study of the autopsy literature. Deep vein thrombosis (DVT) and pulmonary embolism are much more common than usually realized. In a long-range population cohort study, an equal number of venous thrombotic events were discovered after death, at autopsy, as were predicted by death certificate.1 The variability of presentation sets the patient and clinician up for potentially missing the diagnosis. The challenge is that the "classic" presentation with abrupt onset of pleuritic chest pain, shortness of breath, and hypoxia is rarely the case. Studies of patients who die unexpectedly of pulmonary embolism reveal that they complained of nagging symptoms often for weeks before death related to pulmonary embolism. Forty percent of these patients had been seen by a physician in the weeks prior to their death.2 Pathophysiology Pulmonary thromboembolism is not a disease in and of itself. Rather, it is a complication of underlying venous thrombosis. Under normal conditions, microthrombi (tiny aggregates of red cells, platelets, and fibrin) are formed and lysed continually within the venous circulatory system. This dynamic equilibrium ensures local hemostasis in response to injury without permitting uncontrolled propagation of clot. Under pathological conditions, microthrombi may escape the normal fibrinolytic system to grow and propagate. Pulmonary embolism (PE) occurs when these propagating clots break loose and embolize to block pulmonary blood vessels. Thrombosis in the veins is triggered by venostasis, hypercoagulability, and vessel wall inflammation. These 3 underlying causes are known as the Virchow triad. All known clinical risk factors for DVT and PE have their basis in one or more elements of the triad. Patients who have undergone gynecologic surgery, those with major trauma, and those with indwelling venous catheters may have DVTs that start in an area related to their pathology. For other patients, venous thrombosis most often involves the lower extremities and nearly always starts in the calf veins, which are involved in virtually all cases of symptomatic spontaneous lower extremity DVT. Although DVT starts in the calf veins, in cases of pulmonary embolism, it will usually propagate proximally to the popliteal vessels, and from that area embolize.

Frequency United States Venous thromboembolism is a major health problem. The average annual incidence of venous thromboembolism in the United States is 1 per 1000,1,3,4 with about 250,000 incident cases occurring annually. The challenge in understanding the real disease is that autopsy studies show that an additional equal number of patients are diagnosed with pulmonary embolism at autopsy, as were initially diagnosed by clinicians.1,5 This is led to estimates of between 650,000 and 900,000 fatal and nonfatal VTE events occurring in the United States annually. The incidence of venous thromboembolism has not changed significantly over the last 25 years.1 Capturing the true incidence going forward will be challenging because of the decreasing rate of autopsy. In a longitudinal, 25-year prospective study from 1966-1990, autopsy rates dropped from 55% to 30% over the study period.1 Current trends would suggest a continued decline in autopsy rate. However, there is a real challenge in emergency medicine to use these studies to manage an undifferentiated patient in the emergency department. Most of these studies were inpatient or autopsy studies, which arguably are a different patient population than seen in the ED.6 International International journal articles cite similar population incidence of deep vein thrombosis and pulmonary embolism as the United States studies. Mortality/Morbidity Mortality for acute pulmonary embolism can be broken down into 2 categories: massive pulmonary embolism and nonmassive pulmonary embolism. Massive pulmonary embolism is defined as presenting with a systolic arterial pressure less than 90 mm Hg. In two large international studies, this accounted for 4-4.5% of the patients. Nonmassive pulmonary embolism is defined as having a systolic arterial pressure greater than or equal to 90 mm Hg. This is the more common presentation for pulmonary embolism and accounts for 95.5-96% of the patients.7,8 The mortality for patients presenting with massive pulmonary embolism is between 30% and 60% depending on the study cited.9,8,3 The majority of these deaths occur in the first 1-2 hours of care, so it is important for the initial treating physician to have a systemized aggressive evaluation and treatment plan for patients presenting with pulmonary embolism. The diagnosis of massive pulmonary embolism is not solely a function of the size of the clot, rather it is a function of the size of the clot and the functional capability of the patient's cardiovascular system. Hemodynamically stabile pulmonary embolism has a much lower mortality rate, especially in recent years, because of treatment with anticoagulant therapy. In nonmassive pulmonary embolism, the death rate is less than 5% in the first 3-6 months of anticoagulant treatment. The rate of recurrent thromboembolism is less than 5% during this time. However, recurrent

thromboembolism reaches 30% after 10 years.10 Race Studies looking at the incidence of pulmonary embolism in various races show that African American patients are the highest risk group, with a 50% higher incidence than American whites. Asian/Pacific Islanders/American Indian patients have a markedly lower risk of thromboembolism.10,11 Sex Across all age groups, there is a fairly equal distribution of initial pulmonary embolism between males and females.1 However, most studies find that women have a significantly lower rate of recurrent pulmonary embolism.12 Age Venous thromboembolism and pulmonary embolism are diseases associated with advancing age. Furthermore, pulmonary embolism accounts for a larger proportion of venous thromboembolic disease with increasing age for both sexes. This may well be the result of a cumulative effect of risk factors that patients acquire with aging.1,12 Clinical History Pulmonary embolism (PE) is a common condition presenting to the emergency department. A study evaluating patients with potential pulmonary embolism showed 7.2% to be positive for the thromboembolism.13 Symptoms that should lead a provider to consider pulmonary embolism in the differential include chest pain, chest wall tenderness, back pain, shoulder pain, upper abdominal pain, syncope, hemoptysis, shortness of breath, painful respiration, new onset of wheezing, or a new cardiac arrhythmia. Over the years, several scoring algorithms have been developed to help physicians assess the pretest probability of a pulmonary embolism and direct the workup. The 4 most commonly referenced pretest probability models, Wells,14 revised Geneva,15 Charlotte Criteria,16 and the PERC rule17 all use certain historical or physical variables to predict whether or not a patient might have a pulmonary embolism. Clinicians have used these models along with their gestalt and other risk factors to guide their decision-making for evaluation. A multicenter trial sought to validate the "explicit" predictor variables used in the models and also to define other "implicit" variables that normally make up the gestalt that clinicians use along with model variables.13 The historical variables from the models that had a statistically significant predictive value for pulmonary embolism were as follows:

* Previous history of VTE * Surgery within the previous 4 weeks * Estrogen use currently * Active or metastatic cancer * Immobilization The additional variables evaluated that showed a significant predictive value for pulmonary embolism were as follows: * Non cancer-related thrombophilia * Pleuritic chest pain * Family history of venous thromboembolism Physical The physical examination variables from the models that had a statistically significant predictive value for pulmonary embolism were as follows:13 * Unilateral leg swelling * Hypoxemia (saturation 94 beats per minute Examination of the chest is an important part of the physical examination of the patient presenting with a chest or pulmonary complaint; however, there is no specific or significant finding other than tachycardia to point to pulmonary embolism. Massive pulmonary embolism (PE) causes hypotension due to acute cor pulmonale, but the physical examination findings early in submassive PE may be completely normal. After 24-72 hours, loss of pulmonary surfactant often causes atelectasis and alveolar infiltrates that are indistinguishable from pneumonia on clinical examination and by radiography. New wheezing may be appreciated; however, this is usually a later finding. It could also suggest an alternative diagnosis. If pleural lung surfaces are affected, a pulmonary rub may be heard. Causes As stated in the Pathophysiology section, the etiology of venous thrombosis and subsequent thromboembolism results from a distortion in Virchow's triad by venostasis, hypercoagulability, or vessel wall inflammation. These risk factors for venous thrombosis and pulmonary embolism can be broken down into hereditary factors and acquired factors. Hereditary factors (most result in a hypercoagulable state) * Antithrombin III deficiency * Protein C deficiency

* Protein S deficiency * Factor V Leiden (most common genetic risk factor for thrombophilia) * Plasminogen abnormality * Plasminogen activator abnormality * Fibrinogen abnormality * Resistance to activated protein C Acquired factors The most important clinically identifiable risk factors for DVT and PE are a prior history of DVT or PE, recent surgery or pregnancy, prolonged immobilization, or underlying malignancy. * Reduced mobility o Fractures o Immobilization o Burns o Obesity * Old age * Malignancy o Chemotherapy * Acute medical illness o AIDS (lupus anticoagulant) o Behet disease o Congestive heart failure (CHF) o Myocardial infarction o Polycythemia o Systemic lupus erythematosus o Ulcerative colitis * Trauma/major surgery o Spinal cord injury o Catheters (indwelling venous infusion catheters) o Postoperative * Pregnancy o Postpartum period o Oral contraceptives o Estrogen replacements (high dose only) * Drug abuse (intravenous [IV] drugs) * Drug-induced lupus anticoagulant * Hemolytic anemias * Heparin-associated thrombocytopenia * Homocysteinemia * Homocystinuria * Hyperlipidemias * Phenothiazines * Thrombocytosis * Varicose veins

* Venography * Venous pacemakers * Venous stasis * Warfarin (first few days of therapy) Laboratory Studies The challenge of evaluating laboratory studies and pulmonary embolism (PE) is that no one study can provide the answer. Furthermore, ordering a study, such as a D-dimer, must be done with the knowledge that a positive test will most likely result in imaging studies, which involve radiation and contrast load. In a study evaluating the use of the PERC rule to determine the pretest probability of PE, it was found that if the PERC17 rule was used in their cohort, all the following were negative: * Aged younger than 50 years * Pulse rate less than 100 beats/min * Venous oxygen saturation greater than 94% * No unilateral leg swelling * No hemoptysis * No recent trauma or surgery * No previous pulmonary embolism or deep venous thrombosis * No hormone use The pretest probability of PE was 1.4. The conclusion was that low-risk patients who satisfied the PERC rule should not be tested further.18 The white blood cell (WBC) count may be normal or elevated. A WBC count as high as 20,000 is not uncommon in patients with PE. Clotting study results are normal in most patients with pulmonary thromboembolism, although patients with a personal history of noncancer-related thrombophilia show increased risk.13 D-dimer is a unique degradation product produced by plasmin-mediated proteolysis of crosslinked fibrin. D-dimer is measured by latex agglutination or by an enzyme-linked immunosorbent assay (ELISA), and a test result is considered positive if the level is greater than 500 ng/mL.16 A D-dimer screen is best used in conjunction with a clinical assessment of the patient's probability of pulmonary embolism. This can be done systematically using a scoring criteria19,20,21 or in a more gestalt style, basing the probability on the patient's history of predisposing conditions.22 Imaging Studies * The initial chest radiographic findings of a patient with pulmonary embolism (PE) are virtually always normal, although on rare occasions, they may show the Westermark sign (ie, a dilatation of the pulmonary vessels proximal to an embolism along with collapse of distal

vessels, sometimes with a sharp cutoff). o Over time, an initially normal chest radiograph often begins to show atelectasis, which may progress to cause a small pleural effusion and an elevated hemidiaphragm. o After 24-72 hours, one third of patients with proven PE develop focal infiltrates that are indistinguishable from an infectious pneumonia. o A rare late finding of pulmonary infarction is the Hampton hump, a triangular or rounded pleural-based infiltrate with the apex pointed toward the hilum, frequently located adjacent to the diaphragm. * High-resolution multidetector computed tomographic angiography (MDCTA) is the most common study used for detection of pulmonary embolism. o MDCTA has been shown to have sensitivity and specificity comparable to that of contrast pulmonary angiography, and, in recent years, has become accepted both as the preferred primary diagnostic modality and as the criterion standard for making or excluding the diagnosis of pulmonary embolism. o In many patients, multidetector CT scans with intravenous contrast can resolve thirdorder pulmonary vessels without the need for invasive pulmonary artery catheters. o MDCTA is more likely to miss lesions in a patient with pleuritic chest pain due to multiple small emboli that have lodged in distal vessels, but these lesions also may be difficult to detect using conventional angiography. Until recently, nuclear scintigraphic ventilation-perfusion (V/Q) scanning of the lung had been the single most important diagnostic modality for detecting pulmonary thromboembolism available to the clinician. Other alternatives were less sensitive, less specific, or significantly more invasive. Multidetector CT angiography is now a preferred primary diagnostic modality, but the V/Q scan remains an important part of the evaluation when multidetector CT angiography is not available or not appropriate for the patient. * V/Q scanning is indicated when the diagnosis of PE is suspected and CTA is unavailable or contraindicated. o The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) classification scheme allows interpretation of the results of the V/Q scan in a meaningful way. o Diagnostic V/Q patterns classified as high probability or as normal perfusion may be relied upon to guide the clinical management of patients when the prior clinical assessment is concordant with the scan result. * Normal V/Q scan o No perfusion defects are seen. o At least 2% of patients with PE have this pattern, and 4% of patients with this pattern have PE. This means that approximately 1 of every 25 patients sent home after a normal V/Q scan actually has a PE that has been missed. This is unfortunate, but risk-benefit analysis supports the idea that unless the presentation is highly convincing and no alternate diagnosis is demonstrable, a normal perfusion scan pattern often may be considered negative for PE. * High-probability scan o This includes scans with any of the following findings: + Two or more segmental or larger perfusion defects with normal chest radiographs and normal ventilation + Two or more segmental or larger perfusion defects where chest radiographic abnormalities and ventilation defects are substantially smaller than the perfusion defects + Two or more subsegmental and one segmental perfusion defect with normal chest radiograph and normal ventilation

+ Four or more subsegmental perfusion defects with normal chest radiograph and normal ventilation o Forty-one percent of patients with PE have this pattern, and 87% of patients with this pattern have PE. o In most clinical settings, a high-probability scan pattern may be considered positive for PE. * Nondiagnostic scan o This includes scans with any of the following findings: + Small perfusion defects, regardless of number, ventilation findings, or chest radiographic findings + Perfusion defects substantially smaller than a chest radiographic abnormality in the same area + Matching perfusion and ventilation defects in less than 75% of one lung zone or in less than 50% of one lung, with a normal or nearly normal chest radiograph + A single segmental perfusion defect with a normal chest radiograph, regardless of ventilation match or mismatch + Nonsegmental perfusion defects o Sixteen percent of patients with PE have this pattern, and 14% of patients with this pattern have PE. This pattern often is called "low probability," but the term is a misnomer: in a typical population, 1 in 7 patients with this pattern turn out to have a PE. o This scan pattern is an indication for pulmonary angiography or some other definitive test. All patients suspected of PE who have a nondiagnostic scan must have PE definitively ruled out or some definitive alternative diagnosis made. * Duplex ultrasonography o The diagnosis of PE can be proven by demonstrating the presence of a DVT at any site. Sometimes, this may be accomplished noninvasively, by using duplex ultrasonography. o To look for DVT using ultrasonography, the ultrasound transducer is placed against the skin and then is pressed inward firmly enough to compress the vein being examined. In an area of normal veins, the veins are easily compressed completely closed, while the muscular arteries are extremely resistant to compression. o Where DVT is present, the veins do not collapse completely when pressure is applied using the ultrasound probe. o A negative ultrasound scan does not rule out DVT, because many DVTs occur in areas that are inaccessible to ultrasonic examination. Before an ultrasound scan can be considered negative, the entire deep venous system must be interrogated using centimeter-by-centimeter compression testing of every vessel. o In two thirds of patients with PE, the site of DVT cannot be visualized by ultrasound, so a negative duplex ultrasound scan does not markedly reduce the likelihood of PE. Other Tests * Electrocardiography o The most common ECG abnormalities in the setting of pulmonary embolism (PE) are tachycardia and nonspecific ST-T wave abnormalities. The finding of S 1 Q 3 T 3 is nonspecific and insensitive in the absence of clinical suspicion for PE. o The classic findings of right heart strain and acute cor pulmonale are tall, peaked P

waves in lead II (P pulmonale), right axis deviation, right bundle-branch block, an S 1 Q 3 T 3 pattern, or atrial fibrillation. Unfortunately, only 20% of patients with proven PE have any of these classic ECG abnormalities. o If ECG abnormalities are present, they may be suggestive of PE, but the absence of ECG abnormalities has no significant predictive value. * Echocardiography or cardiac ultrasonography23 o The subcostal view is preferred at initial screening for mechanical activity and pericardial fluid and for gross assessment of global and regional abnormalities. To obtain a subcostal view, place the transducer the left subcostal margin with the beam aimed at the left shoulder. o The parasternal view allows visualization of the aortic valve, proximal ascending aorta, and posterior pericardium and allows determination of left ventricular size. It is particularly helpful when the subcostal view is difficult to obtain. To obtain a parasternal view, place the transducer in the left parasternal area between the second and fourth intercostal spaces. The plane of the beam is parallel to a line drawn from the right shoulder to the left hip. o Several echocardiographic findings have been proposed for noninvasive diagnosis of RV dysfunction at the bedside, including RV enlargement and/or hypokinesis of the free wall, leftward septal shift, and evidence of pulmonary hypertension. If right ventricular dysfunction is seen on cardiac ultrasonography, the diagnosis of acute submassive or massive PE is supported. While the presence of RV dysfunction can be used to support the clinical suspicion of PE, prognostic information can be obtained by assessing the severity of RV dysfunction. * Under investigation o Prompt diagnosis and stratification in patients with suspected PE and a high risk of adverse events may help to improve outcomes. Serum troponin, although seemingly marginal for purposes of diagnosis of PE, may contribute significantly to the ability to stratify patients by risk for short-term death or adverse outcome events when they reach the ED. In patients with PE and normal blood pressure specifically, elevated serum troponin level has been associated with right ventricular overload.24,25,26,27 o Elevated levels of brain-type natriuretic peptides (BNP) may also provide prognostic information.26 A recent meta-analysis demonstrated a significant association between elevated N-terminalpro-BNP (NT-pro-BNP) and right ventricular function in patients with PE (p