By Douglas Hill, DO, FACOEP, FACEP

 Emergency physicians are faced with making critical life or death decisions every day in the emergency department (ED). One of the most valuable lessons I have learned on the job is the importance of a strong partnership with the laboratory. Emergency physicians rely on results produced by the lab to make potentially life-saving diagnostic decisions, and it is critical that the lab use the most appropriate diagnostic technology.

Patients enter the ED presenting with any number of symptoms, and it’s imperative that emergency physicians are equipped with the necessary resources to make an accurate and fast diagnosis. New diagnostic technology is introduced to the health care industry every day, and emergency physicians must stay informed about what is in their own labs and demand the best instrumentation.

Many physicians do not even know which methodologies are used in their own labs, and in many cases, results from the appropriate diagnostic testing system can prevent the physician from misdiagnosing or overlooking certain conditions.

Venous thromboembolism (VTE) is a disease commonly misdiagnosed or missed altogether. Deep vein thrombosis (DVT) and pulmonary embolism (PE) represent two points on the continuum of VTE, and because PE has a high rate of mortality, a speedy diagnosis is critical. Many people are surprised to learn that VTE affects more than two million people annually and is the third most common cause of death in the United States. Surprisingly, PE will be missed at least 400,000 times each year, resulting in 100,000 deaths!

Many tests have been touted as gold standards for diagnosing both DVT and PE. There is, however, no specific confirmatory test with both adequate sensitivity and specificity to diagnose both conditions. For example, screening tests need a high level of sensitivity, while confirmatory tests need a high level of specificity.

Fortunately, 75% of patients who present to the ED with suspected VTE do not actually have the condition. For this reason, it is medically prudent to first rule out a diagnosis in patients with low to medium risk factors. The ideal screening test would offer the following characteristics: a negative predictive value (NPV) of 98% or greater, rapid results, demonstrated validity, and a cost-efficient platform. Emergency physicians are most concerned with turnaround time; they view anything greater than 1 hour as being quite limited.

Accuracy in a screening test is another important attribute to the clinician—a screening test with anything less than 98% NPV is simply not acceptable. There are pros and cons associated with each test used to diagnose VTE.

Screening Tests
In the past, the ventilation/perfusion scan (VQ Scan) was the primary screening test to rule in or rule out PE. It is a noninvasive test, but it has poor specificity. Incomplete obstructions, even when produced by large thrombi, may not be detected on a perfusion scan if they do not decrease perfusion to a great degree.

When interpreting the VQ Scan, there are three possible results the radiologist will report: normal, nondiagnostic, or high-probability. Unfortunately, the nondiagnostic result is the most common answer received by the clinician.

In clinical laboratory testing, the standard D-Dimer test measures fibrin degradation products of normal clot lysis. The detection of high levels of D-Dimer is therefore a marker of excess fibrinolysys, following activation of coagulation. Many physicians are comfortable using the D-Dimer assay in their workup of the suspected VTE patient. But some clinicians may not know how to appropriately use the D-Dimer in the workup, or which assay is the best test to use. In fact, I have found that some clinicians do not even know which D-Dimer is used in their own labs. There are several types of D-Dimers, and they are not all created equal.

The standard D-Dimer is the enzyme-linked immunosorbent assay (ELISA), also known as the classic or conventional ELISA. This methodology gives a quantitative value and is extremely accurate. However, it requires sophisticated equipment, runs only in a batched analysis setup, is labor intensive, and involves a lengthy turnaround time. One of the problems physicians face is that the literature, and various institutions, do not use the same techniques or methodologies in screening the VTE patient. The clinician must realize that older medical publications, which reference the ELISA D-Dimer as an accurate but impractical and time-consuming test, are actually referring to this old, classic test.

The Second-Generation, Automated ELISA D-Dimer Assay
The only D-Dimer test found to be helpful as a negative predictor is the second-generation ELISA assay. In our ED lab, we request use of the VIDAS® D-Dimer Exclusion™, a rapid, automated ELISA test. It is highly sensitive, packaged for individual testing, has less than a 1-hour turnaround, and provides accurate, objective, and quantitative results. It is the only methodology that has a specific indication from the Food and Drug Administration (FDA) to rule out both DVT and PE in patients when used in conjunction with a clinical pretest probability (PTP) assessment.

A value less than 500 ng/mL is considered negative. The VIDAS D-Dimer Exclusion’s negative predictive value is documented to be 99+%. Evidence-based critical care and emergency medicine algorithms support this methodology as an end-point in certain patients. The American College of Emergency Physicians’ recently published “Critical Issues in the Evaluation and Management of Adult Patients Presenting with Suspected Pulmonary Embolism” recommends that a negative quantitative ELISA D-Dimer assay as a single test is sufficient to exclude PE in patients with a low PTP of PE. The policy also states that a nondiagnostic VQ Scan and a negative quantitative ELISA will likewise exclude a clinically significant PE in a patient with a low to moderate PTP of PE.

Many labs do not provide this gold-standard assay; rather, they substitute a faster, cheaper, and less accurate version. It is incumbent upon clinicians to know which D-Dimer methodology their labs are using, and to request that labs use a test that meets the ED’s exclusion strategy.

To properly diagnose VTE in a patient, the physician must first estimate the probability that the patient has the disease, which is often done by making a clinical judgment. However, using a clinical prediction rule (such as The Wells’ Criteria for either DVT or PE) is a more precise method to calculate the pre-test clinical probability for the condition. If the patient has a low or moderate PTP of a DVT or PE, then the automated rapid ELISA D-Dimer can be used to exclude those diagnoses. In other words, no further testing is needed. The condition has been ruled out! Finally, ordering a D-Dimer in the face of a high clinical suspicion or a high PTP of DVT or PE is a waste of time and resources, as the diagnostic algorithms point the clinician directly to confirmatory testing.

Confirmatory Testing
Confirmatory tests are conducted once VTE has been determined likely in a patient. While venography has been considered the gold standard to confirm DVT in the past, it is rarely used today. It is an invasive test that is technically challenging, time consuming, and painful.

In recent years, U/S Duplex/Doppler imaging has become the study of choice to diagnose DVT. This test has a high sensitivity and specificity, although it is neither as sensitive nor specific as venography. In the setting of suspected DVT or PE, a positive study of either a noncompressible segment or altered blood flow is enough to make the diagnosis and begin treatment.

Pulmonary angiography is still considered by many to be the gold standard for diagnosing PE. Angiography is invasive, labor intensive, and risky. When performed appropriately, a positive angiogram is excellent evidence that an obstruction exists. A negative study will exclude 90% of cases. False positives may occur when there is an extrinsic obstruction. False negatives have been found in the setting of a small or very distal clot.

The computed tomography (CT) scan is rapidly replacing the VQ Scan as the initial study of choice. In many medical centers, it also is replacing angiography as the definitive test. CT scans are widely available, and the tests take less time to perform than the time it takes to transport the patient to and from the scan suite.

Ancillary Testing
Several ancillary tests are available to support a VTE diagnosis, and they are often used to rule out other conditions. Emergency physicians will likely order a chest x-ray when working up a patient for PE to rule out conditions such as pneumonia. Many chest films in proven PE are actually normal, and when radiographic abnormalities are found, they are nonspecific and insensitive.

Electrocardiogram (EKG) abnormalities in PE are usually nonspecific; the most common finding is a sinus tachycardia. The reported “classic abnormalities” are due in part to right heart strain and may include P pulmonale, right axis deviation, right bundle branch block, and the S1-Q3-T3 pattern.

Arterial blood gasses (ABGs) are neither specific nor sensitive in the setting of PE. In the past, physicians were taught in medical school that ABGs were extremely useful in making the diagnosis of PE, and in fact, a normal blood gas would rule out the diagnosis. This is simply not true! If you are performing an ABG to rule in a PE, there may be another explanation for the signs and symptoms.

Alveolar dead-space measurement is referred to in many publications, but it is not widely available because it is found only in research and academic medical centers. It involves measuring pulmonary function studies while the patient exercises on a treadmill. The results of these measurements are processed, and a value is determined to stratify clinical probability. This test is not very practical.

Physician Pitfalls
Many potential pitfalls can trip up the physician when diagnosing VTE. Reliance on classic signs and symptoms, such as the acute onset of pleuritic chest pain, shortness of breath and hemoptysis, when considering the diagnosis of PE can lead to its missed diagnosis, as only about 20% of patients present with this classic triad. Failure to consider the PTP of having a DVT or PE makes subsequent testing both haphazard and less useful.

The D-Dimer has the greatest utility in its negative predictive value in the context of PTP. The clinician must be familiar with his/her lab’s specific D-Dimer methodology, because only the rapid, automated ELISA can stand alone in excluding a diagnosis of DVT or PE in the low to moderate pretest clinical outpatient. If your lab uses a D-Dimer assay that does not provide rapid, automated results with at least a 98% NPV, then it cannot be utilized as a stand-alone assay in the workup, and further testing must be done.

Automated ELISA D-Dimer exclusion testing is quickly becoming a widely accepted method for ruling out VTE in the ED. A negative D-Dimer test result can prevent patients from undergoing invasive and painful testing procedures and reduce the need for costly confirmatory tests in a significant number of patients.

Douglas Hill, DO, FACOEP, FACEP, is the emergency department staff physician at the North Suburban Medical Center in Denver, and a professor of emergency medicine for the College of Osteopathic Medicine at Kansas City University of Medicine and Biosciences in Kansas City, Mo.