Course Authors
Christopher Kabrhel, M.D.
Dr. Kabrhel is Associate Professor of Surgery, Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Updated by Keith Albrektson, M.D., Ben Alencherry, M.D., and Jihane Faress, M.D.
Dr. Albrektson is Resident, Dr. Alencherry is Chief Resident, and Dr. Faress is Assistant Professor, Department of Medicine, University Hospitals Cleveland Medical Center, Louis Stokes Cleveland VA Medical Center and Case Western Reserve University.
Within the past 12 months, Dr. Albrektson, Alencherry and Faress report no commercial conflicts of interest. Albert Einstein College of Medicine, CCME staff and interMDnet staff have nothing to disclose relevant to this activity.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe how risk factors, signs and symptoms can be used to determine the pretest probability of pulmonary embolism;
Discuss the characteristics of the most commonly used tests for pulmonary embolism;
Describe the different methods to risk stratify patients with pulmonary embolism and understand the importance of risk stratification;
Discuss the indications for low-molecular weight-heparin therapy and thrombolysis.
In this Cyberounds®, we will discuss the diagnosis and treatment of acute pulmonary embolism (PE) in the emergency department. Acute PE represents the most dangerous end of the spectrum of venous thromboembolic disease, which also includes deep venous thrombosis. We will discuss the epidemiology and risk factors for PE and how they can be used to determine pretest probability. We will discuss modern testing and the role of risk stratification in patients diagnosed with pulmonary embolism. specifically the use of the plasma D-dimer and computed tomography. Finally, we will discuss treatment, with a focus on the different options for anticoagulation and the role of thrombolysis.
PE is both an important public health problem and a frequent diagnostic dilemma for emergency physicians. It is estimated that there are between 500,000 and 600,000 cases of acute PE and that PE causes an estimated 50,000 to 200,000 deaths in the United States every year.(1) PE represents about 1/400 of the 110 million emergency department visits each year.(2)(3)
The mortality of acute PE is extremely high. As many as 25% of patients with acute PE present with sudden death.(4) The mortality rate of acute PE, left untreated, has been estimated to be as high as 30%, though more recent studies have suggested that 5% may be a more accurate figure.(5) This makes PE the third most common cause of cardiovascular death in the United States, behind only myocardial infarction and stroke.
Moreover, in the past 20 years, the percentage of emergency department patients evaluated for PE who are ultimately diagnosed with PE has decreased markedly.(6)(7) Unfortunately, this is not because the incidence of PE has decreased but because testing has increased. Emergency physicians who rightly maintain a high index of suspicion for PE will typically test 10-20 patients for every PE they diagnose.(7)
Risk Assessment
The first step in the evaluation of possible PE is the assessment of the patient's risk for the diagnosis. Few studies have examined risk factors for PE alone. In general they are viewed as similar to those for venous thromboembolism (VTE).(8) In the late 19th century, Rudolph Virchow described the triad of venous stasis, hypercoagulability and endothelial injury as the major risk factors for the development of VTE. Today, many factors have been independently associated with the development of VTE, though they can still be thought of in terms of Virchow's three categories (Table 1):
Table 1. Risk Factors for Acute PE.
| Risk Factor | Venous Stasis | Hypercoagulability | Endothelial Injury |
|---|---|---|---|
| Increasing Age | + | + | |
| Prior VTE | + | + | |
| Recent Surgery | + | + | + |
| Paralysis or Limb Immobilization | + | + | |
| Active or Occult Malignancy | + | ||
| Recent Trauma | + | + | |
| Pregnancy | + | + | |
| Estrogen-Containing Medications | + | ||
| Smoking | + | ||
| Obesity | + | ||
| Cardiac Disease/Heart Failure | + | + | |
| Atherosclerotic Disease | + | ||
| Extended Tavel | + | ||
| Peripheral Venous Insufficiency | + | ||
| Acute Infection | + | ||
| Indwelling Venous Catheter | + | + | |
| Inherited Thrombophilias (Factor V Leiden Mutation, Protein C Deficiency, Protein S Deficiency, Antithrombin deficiency, Lupus Anticoagulant, etc.) | + |
The risk factors considered most relevant to ED providers are age >50, prior VTE, recent surgery, limb immobilization, active cancer and estrogen use.(9) The inherited thrombophilia that confers the greatest risk for VTE is a homozygous Factor V Leiden mutation, which increases a patient's lifetime risk of venous thromboembolism by 7-50 times.(10)Protein C and Protein S deficiencies triple the lifetime risk of venous thromboembolism, for a risk of about 2-3% per year.(10) Long-haul travel increases the risk of PE but only by a small amount.(11)(12)
Diagnosis: Pretest Probability
Once the clinician has decided that a patient should be evaluated for possible PE, the next step is to determine the pretest probability of the diagnosis. Accurate pretest probability assessment is critical when deciding which diagnostic tests to use. For example, clinicians may want to measure the serum D-dimer, a breakdown product of cross-linked fibrin released into the bloodstream in the presence of acute thrombus. Or, clinicians may want to order a contrast enhanced CT scan of the pulmonary arteries. These tests are reasonably sensitive but may not be appropriate as stand-alone tests for patients with high pretest probability for PE. This topic will be discussed in more detail later. Finally, clinicians will also combine their pretest probability assessment with the results of these diagnostic tests in order to determine the post-test probability of PE. This Bayesian approach requires clinicians to have an accurate sense of the patient's pretest probability of PE and the test's characteristics (sensitivity and specificity).
Pretest probability can be estimated subjectively simply using clinical gestalt or by using any number of validated scoring methods such as the Wells' Score or the simplified revised Geneva score (sRGS).(13) The subjective gestalt approach has been shown to have similar accuracy to that of the more standardized approaches described below, though experience does seem to improve subjective estimates somewhat.(13)(14)(15)
The most widely referenced PE score was developed by Wells et al. and is commonly referred to as the "Canadian Score" or the "Wells score."(16) The score is comprised of seven questions (Table 2):
Table 2. The Canadian "Wells" Score for PE.
| Question | Points |
|---|---|
| Does the patient have a prior history of PE or DVT? | +1.5 |
| Is the patient's heart rate >100 beats per min? | +1.5 |
| Has the patient had surgery or immobilization in the past month? | +1.5 |
| Does the patient have clinical signs of DVT (leg pain or swelling)? | +3 |
| Has the patient had hemoptysis? | +1 |
| Does the patient have an active malignancy? | +1 |
| Alternative diagnosis less likely than PE? | +3 |
The Wells score has been prospectively validated in several studies.(14)(17) A score of <2 is associated with a pretest probability of PE of about 4%. A score of <4 is associated with a pretest probability of PE of about 5-8%. A score of >6 is associated with a pretest probability of PE of about 33-60%. Generally speaking, patients with Wells score <4 are eligible to have PE ruled out with D-dimer testing alone, though this depends greatly on the D-dimer assay used.
Another prospectively validated scoring method very similar to the Wells score is the simplified, revised Geneva score (sRGS). Much like the Wells score, this tool provides the clinician with a predicted pre-test probability for PE using nine questions (Table 3):
Table 3. The Simplified, Revised Geneva Score for Pulmonary Embolism.
| Question | Points |
|---|---|
| Age >65? | +1 |
| Prior VTE? | +1 |
| Surgery or lower limb fracture in the past month? | +1 |
| Active malignancy? | +1 |
| Unilateral lower limb pain to venous palpation and unilateral edema? | +1 |
| Heart rate 75-94? | +1 |
| Heart rate ??JPY95? | +2 |
| Pain on Limb Palpation? | +1 |
| Hemoptysis? | +1 |
The main difference between the sRGS and Wells score is the sRGS does not require the clinician to use gestalt, leading some to view it as a more objective test.(18) Very similar to the Wells score, patients with an sRGS score of 4 or less are eligible to have PE ruled out with D-dimer testing alone, while patients with scores of 5 or higher should be considered for empiric treatment prior to further diagnostic testing.(9)
One final helpful clinical tool was developed by Kline et al. and is commonly referred to as the "PERC Rule."(18) This eight-factor decision rule was developed specifically to help rule out PE among patients with low clinical suspicion for PE. In patients with a gestalt pretest probability of <15% and a negative PERC rule, no further testing is required, including D-dimer.(20) A prospective multicenter evaluation of the PERC rule showed that the combination of low suspicion and negative PERC rule had a sensitivity of 97.4% for ruling out PE.(21)The eight criteria comprising the rule are seen below in Table 4:
Table 4. The PERC Rule.
| Criteria |
|---|
| Age <50 |
| Heart rate <100 |
| SaO2 ??JPY95% |
| No unilateral leg swelling |
| No estrogen use |
| No prior PE or DVT |
| No hemoptysis |
| No recent surgery or trauma |
A patient meeting all of the above criteria constitutes a negative PERC rule. It is important to remember that despite its overall effectiveness, the PERC Rule does not have 100% sensitivity and will be negative in patients with small PEs at a rate of around one in 100 patients.(22) Overall this test serves as an extremely useful set of criteria to identify low-risk patients who need no further testing.
Diagnostic Assays
Once the clinician has determined a PE can't be ruled out on the basis of clinical gestalt or one of the aforementioned scoring methods, he or she must determine which next diagnostic test makes the most sense. The most important laboratory assay is the quantitative D-dimer. Remember that the D-dimer assay measures peptides deriving from the breakdown of fibrin clots. This assay can be reliably and safely used to rule out PE in patients with low or intermediate pretest probability (e.g., a Wells score or SRGS less than or equal to 4).(23)(24)
It is important to note, however, that there are many different analytical techniques used to measure D-dimer and the test characteristics (i.e., sensitivity and specificity) of each individual assay can vary greatly depending on the assay used. D-dimer assays can be grouped into three categories based on the manner in which they obtain the final test result: enzyme-linked immunosorbent assays (ELISA), agglutination techniques, or fluorescence assays.(25)
In addition to variable analytical techniques, the reporting of D-dimer results is extremely variable. Most labs report in either D-dimer mass concentration (e.g., nanograms per milliliter or micrograms per milliliter) or fibrinogen equivalent units. A recent international study showed wide variability in terms of units of measurements used for D-Dimer reporting both in the United States and abroad.(26)It is crucial that clinicians know which assay is used in their hospital laboratory and understand the unit of measurement prior to making clinical decisions based on the results.
Two commonly used quantitative D-dimer assay techniques are ELISA and immunoturbidimetric latex agglutination. These tests have a sensitivity of around 96% and 93% respectively.(26)(27)Unfortunately, the specificity of both the aforementioned assays and most D-dimer assays in general is relatively low at around 45%. This means many patients without PE will have positive D-dimer results and require radiological imaging. This is by far the most significant limitation of the D-dimer assay. Given the low specificity of this test, it is important to know the most common causes of false positives. They are listed below in Table 5:
Table 5. Causes of False Positive D-Dimer.(28)
| Causes of False Positives | Odds Ratio |
|---|---|
| Increasing age (60-69, 70-79, ??JPY80 yrs.) | 2.6, 4.5, 10.5 |
| Immobility | 2.3 |
| Hemodialysis | 2.2 |
| Active malignancy? | 2.6 |
| Pregnancy (2nd trimester, 3rd trimester, postpartum) | 7.3, 51.3, 4.2 |
| Orthopedic surgery <4 weeks prior? | 2.2 |
| Systemic Lupus Erythematosus | 2.1 |
| Rheumatoid Arthritis | 2.8 |
| Cocaine use | 2.0 |
Increasing age is one of the more important and often unrecognized causes of a false positive D-dimer. Many clinicians have suggested using age-adjusted cutoffs in order to improve the specificity of the test in elderly patients. Multiple studies have shown that upward age-adjustment of D-dimer values maintains adequate exclusionary ability in patients with low to moderate pre-test probability for PE.(29) Despite its demonstrated effectiveness, the use of age-adjusted D-dimer values remains rare in the United States and abroad.(26)
Diagnostic Imaging
All patients with an elevated D-dimer and a high pretest probability for PE must undergo diagnostic imaging next. Computed tomography pulmonary angiography (CTPA) has effectively supplanted other modalities as the first imaging test for suspected PE. The test requires the patient to lay flat and hold their breath for a few seconds while a machine injects around 120 mL of contrast via a peripheral or central venous catheter.(30)
A good quality CTPA can actually rule out a PE at all pretest probabilities. Multiple studies have shown that CTPA has an extremely high negative predictive value (NPV), ranging from 98.7% – 99.9% across all patient populations.(31) One meta-analysis and systematic review examined the NPV of CTPA in patients with a high or likely clinical probability for PE and found that the NPV was still extremely high at 98.8%. The authors also examined the utility of performing compression ultrasonography following a normal CTPA and found that it did NOT improve diagnostic utility.(32) Despite the obvious utility of this test, it is important to remember the risks that CTPA can pose to patients. These risks include over-diagnosis of PE, kidney injury, radiation exposure and anaphylactic contrast reactions amongst other things.(30)
Improvements in CT scanning technology have also led to the increased detection of isolated subsegmental PEs.(33) These subsegmental PEs are filling defects seen in a single small pulmonary artery. Not only are these small PEs difficult for radiologists to diagnose and often missed, but they also provide a dilemma when it comes to treatment.(34) The topic of whether or not to treat isolated subsegmental PEs is a controversial one and conflicting data currently exists. To date there has been no randomized trial examining the safety of withholding anticoagulation for subsegmental PEs. Most guidelines favor treatment of patients with subsegmental PEs especially when there are persistent risk factors for VTE such as active cancer or likelihood for ongoing immobilization.(30)
In conclusion the CTPA is an extremely useful test and has greatly improved the ability for clinicians to diagnose pulmonary emboli. However, the test is not without harm and should be used in the right clinical context to avoid both patient harm and overburdening of the healthcare system.
Other tests that can be useful when a CTAP is contraindicated is ventilation perfusion scan or magnetic resonance pulmonary angiography
Risk Stratification
Once the diagnosis of pulmonary embolism is made, it becomes important for the clinician to determine which patients need closer monitoring as an inpatient and which patients can be discharged home with oral anticoagulation and close follow-up. Multiple prognostic models have been developed to this end with the most well-known being the Pulmonary Embolism Severity Index (PESI) and its cousin the simplified PESI.(35)(36) The PESI uses eleven clinical criteria to risk stratify patients into five classes based on 30-day mortality rates. The sPESI uses just five clinical criteria to group patients into either a low-risk for mortality group or a high-risk for mortality group. The components of each test are summarized below in Tables 6 and 7:
Table 6. PESI.
| Clinical Feature | Points |
|---|---|
| Age | X (e.g., 65) |
| Male gender | 10 |
| History of cancer | 30 |
| Heart failure | 10 |
| Chronic lung disease | 10 |
| Systolic blood pressure <100 mm Hg | 30 |
| Respiratory rate ??JPY30/min | 20 |
| Temperature <36o C | 20 |
| Altered mental status | 60 |
| Arterial oxygen saturation <90% | 20 |
| Class I – Very Low Risk | <66 |
| Class II – Low Risk | 66-85 |
| Class III – Intermediate Risk | 86-105 |
| Class IV – High Risk | 106-125 |
| Class V – Very High Risk | >125 |
Table 7. sPESI.
| Clinical Feature | Points |
|---|---|
| Age >80 years | 1 |
| History of cancer | 1 |
| Chronic cardiopulmonary disease | 1 |
| Pulse ??JPY110/min | 1 |
| Systolic blood pressure <100 mm Hg | 1 |
| Arterial oxygen saturation <90% | 1 |
| Low Risk | 0 |
| High Risk | ??JPY1 |
The PESI and sPESI models provide the clinician with a useful tool to risk stratify patients. Since its creation the PESI has been prospectively validated in a large cohort of European patients. Patients in PESI classes I and II have a 30-day mortality of 1.1% and 3.1% respectively and can generally be managed with outpatient coagulation or early discharge home following initiation of anticoagulation. Patients in classes III, IV and V have 30-day mortalities of 6.5%, 10.4%, and 24.5%, respectively. These patients should be monitored more closely with consideration of ICU-level care and advanced therapies for those at highest risk.(38)
The sPESI was derived from the PESI score in an effort to decrease the time and effort needed to risk stratify patients in busy and hectic clinical environments. While it has not been prospectively validated to date, it appears to have similar prognostic accuracy to the PESI and divides patients into two simple groups: high risk and low risk. The 30-day mortality is around 1% for low risk sPESI patients and around 9% for high risk sPESI patients. Similar to the PESI, low risk sPESI patients can generally be thought of as good candidates for outpatient therapy, while high risk sPESI patients should be monitored more closely.(37)
There is still much to learn when it comes to risk stratifying patients with pulmonary embolism. While the PESI and sPESI are currently the most validated and updated, there are at least 15 other prognostic models in existence. Many of these models show great potential and utilize both biomarkers and imaging-based criteria. Newer prognostic models focus on further risk stratifying intermediate risk patients and will be of great use to clinicians if they prove successful.(39)
Treatment Strategies
Patients diagnosed with PE require emergent treatment that is both supportive and directed. With adequate supportive therapy and anticoagulation, the mortality of PE drops from as high as 25% to 5-10%.(5) Acute PE causes an increase in dead space ventilation, the release of inflammatory mediators, ventilation/perfusion mismatch, increased pulmonary artery pressure and may result in acute right heart failure. It is therefore important to augment both oxygenation and pre-load (with IV fluids) in patients with acute PE.
For decades, the standard treatment for acute PE was anticoagulation with intravenous unfractionated heparin (UFH) and in many cases it still is. Dosing should be based on the patient's weight: typically with a loading dose of 80 U/kg followed by an 18 U/kg/hour infusion. The infusion should be titrated to a goal partial thromboplastin time (PTT) of 60-80 seconds.
More recently, low-molecular-weight heparin (LMWH), direct oral anticoagulants (rivaroxaban and apixaban), and synthetic heparin analogues (fondaparinux) have been shown to be safe and effective alternatives to unfractionated heparin. A recent systematic review and meta-analysis compared the safety and efficacy of UFH + coumadin, LMWH + coumadin, Fondaparinux + Coumadin, LMWH + dabigatran, LMWH + edoxaban, rivaroxaban alone, apixaban alone and LMWH alone. This study found no statistically significant differences for safety or efficacy between the eight treatment options when compared to the LMWH + Coumadin combination. The study also found that apixaban and rivaroxaban may be associated with the lowest risk for major bleeding events and that the UFH + Coumadin might be the least effective strategy.(40)
With the multitude of options currently available to treat acute PE, the clinician should be aware of patient populations or risk factors that warrant choice of a specific anticoagulant. Such populations include patients with renal failure, patients with malignancy, pregnant patients, patients with a prior history of HIT and patients with hemodynamic instability. Patients with renal failure and hemodynamic instability should be treated with IV UFH. IV UFH requires no renal adjustment and can be quickly turned on and off in the event that thrombolysis or an interventional procedure is required. Multiple studies have shown the benefit of LMWH in the treatment of acute PE in patients with malignancy. Pregnant patients should be treated with LMWH given its favorable safety profile. Finally in patients with a prior history of HIT, Fondaparinux is the preferred agent for treating an acute PE.(41)
For patients with very large PE, or limited hemodynamic reserve, anticoagulation and supportive care may not be sufficient. Options for treatment at this stage include thrombolytic agents, which be delivered systemically or locally via catheter, and embolectomy either surgically or via catheter. Current guidelines recommend systemic thrombolytic therapy only in patients with acute PE who are hemodynamically unstable (SBP <90), and no increased risk for bleeding.(42)(43) However, in select patients with PE and signs of clinical deteriorations on systemic anticoagulation, but no hypotension, it may be appropriate to use systemic thrombolytic therapy.
Catheter directed thrombolysis and embolectomy are advanced therapies not widely available to many patients with PE. Current guidelines suggest the use of catheter directed thrombolysis in patients with PE, increased risk of bleeding and hypotension in areas where the expertise and resources are available. Embolectomy, either surgical or catheter-directed, is rarely performed and recommended only in patients who have PE and have either failed systemic thrombolysis, contraindications to thrombolysis, or severe shock likely to cause death prior to systemic thrombolysis taking effect.(41)(42)
Many of the interventional therapies available for acute PE have very specific indications and the decision about which therapy to use can be a difficult one to make. For this reason many large medical centers have developed interdisciplinary teams that can be called upon on short notice to appropriately triage patients with acute PE and decide on the best treatment modality.(43) This is an exciting step forward in the management of pulmonary emboli.
Summary
PE is a common and potentially fatal disease that affects several hundred thousand Americans every year. The diagnosis of PE is complex and involves a combination of pretest probability assessment and diagnostic testing. Subjective and objective methods for pretest probability assessment are available. The most commonly used diagnostic tests for PE include D-dimer blood assays and CT scanning of the pulmonary arteries, though each modality has limitations. Once PE is diagnosed the patient should be risk-stratified and acute treatment, including supportive therapy and anticoagulation, should be offered. Thrombolysis is effective for treating PE, but it has only been shown to clearly benefit hemodynamically unstable patients.