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PERFUSION SCINTIGRAPHY
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VENTILATION/PERFUSION SCINTIGRAPHY Alan M. Kumar, MD, and J. Anthony Parker, MD, PhD
Lung scintigraphy does not primarily image pulmonary emboli (PE) but rather images the physiologic effects of PE on regional ventilation and perfusion. When a PE obstructs pulmonary blood flow to a region of the lung, the ventilation to this region usually remains normal, giving a ventilation/perfusion (V/Q) mismatch. Regions of the lung with decreased ventilation because of airway disease have reflex vasoconstriction, to prevent shunting of unoxygenated blood to the systemic circulation, giving a V/Q match. The region of altered physiology is much larger than the embolus itself and thus is easily visualized using the relatively low resolution of scintigraphy. Furthermore, evaluation of the altered physiology can provide useful information about the severity of the process. Lung scintigraphy is not always able to identify uniquely the pathologic process from evaluation of the physiologic effects of the process, however. For example, regions where the chest x-ray, perfusion scan, and ventilation scan are all abnormal (sometimes called a triple match) can be due to either a primary pulmonary process or to an embolus with infarction. After describing the relevant lung physiology, this article explains how the findings on lung scintigraphy are interpreted and used to provide information about the diagnosis of PE. HISTORY
The first nuclear medicine studies of the lung used radioactive gas to assess regional ventilation in lung ~ a n c e r Taplin .~ et a1 developed From the Harvard Affiliated Emergency Medicine Residency, Department of Emergency Medicine, Brigham and Women’s Hospital (AMK); and Division of Nuclear Medicine, Department of Radiology, Beth Israel Deaconess Medical Center (JAP), Boston, Massachusetts
EMERGENCY MEDICINE CLINICS OF NORTH AMERICA VOLUME 19 * NUMBER 4 NOVEMBER 2001
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macroaggregated albumin particles labeled with I'31 to measure regional pulmonary blood flow, and Wagner et a1 applied perfusion scanning to the diagnosis of PE.2-3Simultaneous evaluation of perfusion and ventilation by radioactive gas and subsequently by radioactive aerosol was used to increase the specificity of the diagnosis of PE.I3The size, multiplicity, character, and correspondence of defects on perfusion scan, ventilation scan, and chest x-ray were combined into diagnostic schemes by McNeil et al, Biello et al, and the PIOPED investigators.', 7, Most comparisons of lung scintigraphy and pulmonary angiography have suffered from referral bias owing to the small fraction of patients who go on to pulmonary angiography after lung scan. Because of the high rate of arteriography, the authors' focus here is on reviewing the results of the PIOPED study for the comparison of lung scintigraphy and pulmonary arteriography.
ANATOMY AND PHYSIOLOGY
The airways display a branching pattern from the trachea down to the terminal respiratory units or alveoli. The typical adult has about 250 to 300 million alveoli, each with an average diameter of 150 pm. Although the direct anatomic pathway is the most common route of air to the alveoli, alternative routes such as the pores of Cohn (between neighboring alveoli), and the canals of Lambert (between bronchioles and alveoli) are sometimes used to prevent the collapse of an obstructed segment. The trachea divides into the right and left mainstem bronchi. The right mainstem subdivides into the right upper, middle, and lower lobe bronchi. The left mainstem subdivides into the left upper and lower lobe bronchi. Each lobe is divided further into segments, eighteen in all (Fig. 1). The main vascular supply to the lungs, the pulmonary arteries, divide in a branching pattern similar to the airways following the bronchi to the level of the alveoli. The capillaries surrounding each alveolus have an average diameter of 7 to 10 pm. The arterial blood supply to the lungs is from two to four bronchial arteries, originating from the aorta. They anastomose with the pulmonary circulation at the capillary level. Ventilation and perfusion are both significantly affected by gravity and patient position. In the upright position, the apices receive one half of the perfusion of the bases. In the supine position, there is more of an equal distribution of blood flow. There is an increased relative flow to the dependent portions of the lungs, however. Because of gravity, the upper zones of the lungs have greater negative intrapleural pressure. This supplies more tethering support to the alveoli in that region, and they tend to remain open during expiration. Conversely, the alveoli in the lower lung zones are more likely to collapse and open during the alternating phases of respiration. Because of the increased change in potential volume at the lower zones, gas exchange is much greater at
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Figure 1. Segmental anatomy of the lung. Left upper lobe: A-1 , posterior apical segment; A-2, anterior segment; A-3, superior lingular segment; A-4, inferior lingular segment. Left lower lobe: B-1, superior segment; 8-2, anteromedial segment; B-3, lateral basal segment; 8-4, posterior basal segment. Righf upper lobe: C-1, apical segment; C-2, posterior segment; C-3, anterior segment. Right middle lobe: D-1, lateral segment; D-2, medial segment. Right lower lobe: E-1, superior segment; E-2, posterior basal segment; E-3, lateral basal segment; E-4, anterior basal segment. (From Rosen P [edl: Emergency Medicine: Concepts 2, ed 4. St Louis, MO, Mosby, 1998; with permission.) and Clinical Practice, VOI
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the bases. In a healthy adult patient, ventilation at the base is 150% of that at the apex. Ventilation and capillary perfusion should match for efficient gas exchange. Autoregulatory mechanisms exist in the lungs to cause local vasoconstriction is areas of hypoventilation, resulting in redistribution of blood flow away from that area. When there is local ischemia, however, ventilation rarely changes. In humans, bronchoconstriction and shifting of ventilation away from the ischemic region is transient and uncommonly seen. Patients with a PE should have normal ventilation scans, barring secondary complications. PERFUSION IMAGING
Perfusion imaging is based on the principle of capillary blockade. Virtually all perfusion studies are performed using T~~~~-macroaggrein diameter gated albumin (Tc99m MAA), a particle usually 10 to 9 0 ~ m with a 6-hour physical half-life and a 2 to 9 hour biologic half-life. It is prepared by denaturing human serum albumin. The radiopharmaceutical is injected intravenously and mixes uniformly with venous blood by the time it reaches the right heart. Many tracer particles are larger than the capillaries in the lung and lodge in the precapillary arterioles. Fewer than 0.1% of the capillaries are usually blocked. The distribution of tracer usually correlates to the various pulmonary segments. Images are collected in up to eight positions (i.e., anterior, posterior, right and left lateral, right anterior and posterior oblique, and left anterior and posterior oblique) on a large field of view gamma camera. The best images are obtained in the upright position, where the lungs are most expanded and there is the least diaphragmatic motion. Segments with defects in perfusion create images with corresponding areas of decreased tracer uptake. This process mimics that of pulmonary embolization but can also be caused by other conditions such as pneumonia, effusion, and bullae. VENTILATION IMAGING
Unlike perfusion imaging, there are a few choices of ventilation radiopharmaceutical agents. One commonly used is Xe133,which is an inert gas with a 5.2-day physical half-life and a 1-minute biologic halflife. It circulates into the lung through normal ventilation similar to room air. The distribution of Xe133after a single breath shows lung ventilation. The number of counts that can be collected during a single breath is low, however, so the images are of relatively low resolution. Exhaled radioactive Xe133gas can be trapped using an activated charcoal filter, but some gas can leak into the room, particularly with sick patients. Ventilation studies must be performed in negative-pressure rooms and with the exhaust placed low in the room to capture the gas, which is heavier than air.
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Advantages to Xe133include price, easy availability, and the ability to perform inspiration, equilibrium, and wash-out phases. The singlebreath image is more sensitive, for large regions of mild to moderately reduced ventilation, and the wash-out images are more sensitive, for smaller regions of markedly reduced ventilation. Using all three phases provides the most sensitive ventilation study for evaluation of airway disease. XelZ7,which is similar to Xe133,has more favorable imaging characteristics, but because of higher cost of production, it is not commercially available. Because of the very short half-life of Krsl (13 seconds) it decays before coming to equilibrium. Good-quality images can be collected during tidal breathing with an isotope distribution similar to a single breath image. KrS1does not allow equilibrium or wash-out phases and, like XelZ7,has limited availability. The ventilation study is performed in the posterior projection to cut down on artifact created from soft tissues and to maximize the number of pulmonary segments seen. During wash-out, posterior oblique images are also obtained. In a typical Xe133ventilation scan, the patient is fitted with an airtight mask and run through the three phases previously mentioned. An initial deep inspiration phase has the patient take as deep a breath as possible and hold while the camera collects the image. The second phase has the patient breathing an air-Xe133mixture for 3 to 5 minutes in a closed system to collect an equilibrium image. The final phase involves providing fresh air to the patient to "wash-out" the xenon gas and obtain images to evaluate for gas trapping, an indication of obstructive lung disease. This test requires extensive patient cooperation and participation, which can limit the ability to perform a quality study. Technetium-labeled aerosols also can be used to image ventilation. They are similar to Krs1 in that they do not allow for wash-out images or dynamic single-breath imaging. Because T c ~ ~is" used for both the aerosol and the MAA, using a lower dose for the first procedure and a higher dose for the second procedure reduces the interference between images. Technetium-labeled aerosols are easier to prepare, administer, and image. There is no special venting required after Tc is used, and it can be used portably if necessary. Patient cooperation for special breathing is unnecessary, allowing a simpler method of administration. CLINICAL APPLICATIONS The indications for ordering a V/Q scan are limited. The most common reason is to assess for the probability of PE in a patient with clinical symptoms. It can also be ordered to assess for PE in patients without clinical symptoms of a blood clot in the lungs, but with a newly documented deep vein thrombosis (DVT) and for whom a positive V/ Q scan would change the management. It can also be performed just prior to resolution of anticoagulation therapy to have a new baseline of comparison if the patient were to have new symptoms. V/Q scans can
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also be used to assess lung function prior to resection for lung cancer, prior to lung volume reduction surgery, or after transplantation. Tc99m MAA scanning can be used to assess right-to-left shunts. In the emergency department (ED) the assessment of probability of a PE is the most common reason to order a V/Q scan. In a patient with a clear chest radiograph, the V/Q scan is the study of choice for evaluation of PE embolism because it is noninvasive and carries a minimal risk of complications. When chest x-ray findings make it likely that the lung scan will not provide a clear answer, many clinicians choose CT angiography as the first choice (see elsewhere in this issue). Although there are no absolute contraindications to performing a V/Q scan, the study is not completely without risk, and there are certain relative contraindications that must be considered before proceeding. Tc99m MAA has a short half-life and fragments before leaving the lungs, being removed from the circulation by the reticuloendothelial system. In patients with right-to-left shunts, a large number of unfragmented particles can enter the systemic circulation. There have been no documented adverse effects from systemic MAA particles, and MAA has been used to evaluate right-to-left shunts, but theoretically, they could cause adverse effects on the cerebral and coronary circulation. In patients with severe pulmonary hypertension, the Tc99mMAA molecule's obstruction of preterminal arterioles has been reported to exacerbate the condition acutely and lead to complications. Also, care should be taken in patients with documented hypersensitivity to human serum albumin, a building block for T c ~ ~MAA. " In pregnant patients, the administered activity can be reduced if the patient can tolerate a somewhat longer procedure. The radiation dose to the fetus is small, and the risk-to-benefit ratio is low for indicated studies. When one requests a V/Q scan, the radiologist interpreting the study needs certain information. The radiologist should be considered a consultant who will interpret the study based on the particular patient being presented. The emergency physician should convey the clinical history, noting symptoms of chest pain, dyspnea, hemoptysis, and syncope, and discuss abnormal vital signs. Age, risk factors for PE, as well as symptoms or a known recent diagnosis of DVT should be presented. Previous medical history, especially that which could affect the V/Q scan images and interpretation, such as prior PE, congestive heart failure, chronic obstructive pulmonary disease, radiation therapy, or asthma, should also be conveyed. A chest x-ray should be obtained in every patient prior to proceeding to V/Q scan, because it can sometimes change the differential diagnosis. It is also an essential component in the proper interpretation of the V/Q scan. The plain radiograph should have been performed within the past 12 to 24 hours to better define the spatial characterization of the lungs before the V/Q scan can produce a functional assessment with which to compare it. Any other recent studies, such as compression ultrasonography of the lower extremities or a CT angiogram, also should be discussed with the consulting radiologist.
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V/Q INTERPRETATION Normal Scans
A normal perfusion scan is shown in Figure 2. There is normally a gradient from the apex to the base that is caused by the increased perfusion at the base. There is an obvious defect created by the cardiac silhouette and aortic knob in the anterior image, although they are noticeable in multiple other images as well. The lateral images, and to a lesser degree, the oblique images, have overlap between the lungs. Up to one third of the scintigraphic image can come from the superimposed lung, thereby obscuring significant perfusion defects seen in other views. Subtle abnormalities unrelated to the lung parenchyma can cause defects in an otherwise normal perfusion scan. Cardiomegaly, tortuosity of the aorta, and mediastinal or hilar prominence can cause defects along the medial border of the lung. Small pleural effusions can blunt the posterior sulci or create a linear defect along the region of the major fissure, termed the fissure sign. Moderately sized effusions occasionally can mimic segmental defects. Incidental segmental and subsegmental defects can be seen in up to 7% of healthy young asymptomatic people, and that percentage rises in smokers. There is no way to be certain of the cause of these seemingly benign defects, because on occasion multiple small emboli have been documented to simulate these conditions on scintigraphic images. A normal ventilation scan is shown in Figure 3. After the initial inspiratory phase, a relatively homogenous distribution of radiotracer
Figure 2. Normal perfusion scan. A cardiac impression on the anterior views. There is a gradient in intensity from apex to base and from anterior to posterior. There is a slight decrease in activity over the hilar regions due to region occupied by the bronchi and vessels. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique.
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Figure 3. High likelihood ratio scan. A six-view perfusion scan is shown on top and ventilation scan is shown on bottom. The perfusion scan shows marked abnormalities in both lungs. The only relatively normal perfusion is seen in the anterior and apical posterior segments of the left upper lobe. There is some perfusion in the right lung; however, in comparison to the left upper lobe it can be seen that there is markedly decreased perfusion throughout the entire right lung. The ventilation study in the posterior projection is normal. The initial breath image that represents ventilation should be compared to the posterior view on the perfusion scan. The initial breath image is followed by several equilibrium images. The last row shows wash-out and finally a delayed trapping image. Note that this ventilation study was performed after the perfusion and there is shine through of the perfusion activity in the ventilation images, most clearly seen on the delayed trapping image. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique, IB = initial breath, Eq = start of equilibrium, WO = start of wash-out, Trap = trapping image.
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occurs. The equilibrium phase image should match the inspiratory image in normal patients, although the inspiratory phase has less activity. The wash-out images should show clearance of the gas, usually within 3 minutes. Wash-out is the most sensitive phase for the detection of trapping. Retention of xenon is indicative of obstructive disease. Xenon gas is also soluble in fatty tissue and, to a lesser degree, blood. Images taken in the posterior position minimize artifact from breast tissue. A seeming abnormality at the base of the right lung can sometimes be due to fatty liver with increased activity. Air swallowing, especially in pediatric patients, can also produce activity in the stomach that projects onto the collected images. Ventilation images usually are obtained first to prevent background activity from the perfusion study when one is using Xe133.An advantage of XelZ7and Krsl is the ability to do postperfusion images, which allows one to choose the projection to collect ventilation images that best evaluate a defect in a particular region or segment during the preceding perfusion scan. Abnormal Scan Result
An abnormal scan result is defined as either a ventilation or perfusion study that has focal areas of defect or inhomogeneity of radiopharmaceutical distribution. Clinically significant PEs cause obstruction of arterial blood flow to an affected lobe segment, or less commonly, subsegment. When a patient undergoes a V/Q scan, the T c ~ ~ MAA " distributes evenly throughout the capillaries except in the obstructed segment, where the clot prevents downstream passage of the radiotracer, resulting in a segmental defect on a perfusion scan. The abnormal blood in the affected segment does not alter the regional ventilation; therefore, the ventilation images collected should remain unaffected. This disassociation between a typically wedge-shaped perfusion defect corresponding to a pulmonary segment with preserved ventilation leads to the classic manifestation of pulmonary embolus: the segmental V/Q mismatch. Focal areas of deficit on a perfusion scan can be caused by myriad conditions: PE Pneumonia Pulmonary edema Pleural effusion Radiation therapy Atelectasis Vasculitis Primary tumor or metastasis Pulmonary fibrosis Localized hypoxia secondary to asthma, bronchitis, or emphysema Perfusion defects are categorized as segmental or nonsegmental, depending on whether they correspond to a known bronchopulmonary
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anatomic segment. Nonsegmental defects do not correspond to known anatomic segments and are usually not wedge shaped. Possible causes of nonsegmental defects significantly overlap those of segmental defects. Classically, PEs are segmental, so that the ability to differentiate between the two is crucial in assigning a likelihood ratio. Pulmonary embolic defects extend to the periphery of the lung, whereas many other pulmonary processes can spare the periphery. Perfusion at the periphery of a defect, called a stripe sign, suggests a nonembolic cause. The shape, location, and size of the defect should be compared in multiple views of the scan to see if it fits with a known anatomic segment. Size is classified further into small (<25% of the segment), moderate (25%75%), or large (>75%). The size and number of defects are used within a set of interpretation criteria to assess the probability of the abnormalities representing a PE. In the PIOPED criteria, large defects are counted as 1 segmental equivalent; moderate defects are counted as 0.5 segmental equivalents; and small defects are not counted. The location of the defect in relation to the upper, middle, or lower zones of the lungs also play a role in the rite ria.^ The perfusion scan is also compared to the ventilation scan, and vice versa. Any perfusion defect should be compared to the corresponding region on the ventilation scan (see Fig. 3). A mismatch exists if there is a normal xenon image. A match exists if there is a ventilation abnormality in the same region. Although a mismatch is the key interpretive finding, the size, number, and location of defects have a role in the interpretive schema. The V/Q-matched defect should also be compared specifically to the chest x-ray to see if the radiograph also shows a matching abnormality. This occurrence is called a triple match. A triple match can be caused by a primary parenchymal process, leading to decreased ventilation and secondarily decreased perfusion. A PE with infarction has primarily decreased perfusion with secondary air space filling and decreased ventilation, but the result is also a triple match. V/Q INTERPRETIVE CRITERIA
The radiologist’s reading of a V/Q scan is based on a set of interpretive criteria that assigns a likelihood ratio for the scintigraphic findings. The likelihood ratio is combined with the prior probability of PE to produce a posterior probability. Scans are defined as falling into one of five major criteria: normal, very low, low, intermediate, and high likelihood ratio for PE. Traditionally, the word probability has been used for scan results (e.g. high probability scan). When describing the results of the PIOPED study the authors follow this conventional usage; elsewhere, they follow the recommendation of the Society of Nuclear Medicine Procedure Guideline for Lung Scintigraphysaand use the more accurate term for a test result, likelihood ratio. Given a typical prior probability of disease, a high likelihood ratio scan indicates a greater than 80% poste-
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rior probability of PE. Intermediate scans give a probability of 20% to 8O%, to and low likelihood ratio scans give a probability below 20%. A very low likelihood ratio places the posterior probability at below 5%. When the chest x-ray, perfusion scan, and ventilation scan are all abnormal (a triple match), a PE with secondary infarction cannot be distinguished from any other cause of infiltration. In this case, the lung scan is often called indeterminate for PE. Over time, multiple criteria models were developed and modified, the most common being the modified Biello criteria.' In the late 1980s, a multimillion dollar multicenter trial was undertaken for the prospective investigation of PE diagnosis (PIOPED). PIOPED was designed to compare V/Q scans for acute PE using a predetermined set of interpretive criteria with pulmonary angiography. Over the past 10 years, the PIOPED and the modified PIOPED criteria have become the most widely used interpretive schemes.2, PIOPED was able to study 931 patients who had V/Q scans for acute PE, 755 of whom also went on to have pulmonary angiograms. Of the 176 patients who did not have angiograms, 136 had scan readings of low probability or normal/near normal. In follow-up study, none of these patients were treated with anticoagulation or developed clinically evident PE. Of the 755 patients who did have angiograms, an additional 24 were removed for technical difficulty or inability to interpret the angiogram to a high degree of certainty. Table 1 the results of the remaining patients with V/Q scans and angiograms. The final group of patients was selected from a group of more than 5500 patients in whom a lung scan was requested. Although the study design evaluated every patient for enrollment, the characteristics of the final group still had some selection bias. The 1-year mortality of the final group of patients was very low. Usually, the death rate in a year for a group of patients referred for lung scan is over 10%; most patients dying 6, The prior probability of PE was also of their underlying di~ease.~, higher than in most hospitals. At the Beth Israel Deaconess Medical Center in 1998, the incidence of high or moderately high likelihood ratio readings was 7%; in the PIOPED study, the incidence of high probability scan was 16%. Thus, the PIOPED patients had fewer serious underlying conditions, and they were more likely to have PEs than the average patient. Table 1. RESULTS OF PIOPED STUDY ~~
Scan Result
Angiogram Results Positive for PE
Angiogram Results Negative for PE
High Intermediate Low Normal Totals
102 105 39 5 251
14 217 199 50 480
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The criteria used in PIOPED have been modified since the original study and are listed here: High Probability: >SO% Two or more large mismatched segmental defects without a radiographic abnormality (or the perfusion defect is substantially large than the radiographic abnormality) Any combination of mismatched defects equivalent to the above (two moderate defects, one large defect) Intermediate Probability: 20% to 80% One moderate mismatched segmental defect with a normal radiograph One large and one moderate mismatched segmental defect with a normal radiograph Difficult to categorize as high or low probability Not meeting the stated criteria for high or low probability Low Probability: <20% Nonsegmental perfusion defects Any perfusion defect substantially smaller than a corresponding radiographic abnormality Matched ventilation and perfusion defects with a normal chest radiograph Small subsegmental perfusion defects Normal: No perfusion defects The PIOPED investigators chose to define specific criteria for high and low probability, with all other defects falling into an intermediate category. Only the classic presentation of multiple large and moderate segmental perfusion defects with a normal ventilation scan would qualify as high probability in a patient with a normal chest x-ray. If the perfusion defect is substantially larger than the area of opacity on plain radiography, this also qualifies as high probability. This degree of strictness in assigning the high likelihood category is based on the fact that PEs are multiple in 90% and bilateral in 85% of cases. Perfusion abnormalities in relation to an opacity on chest x-ray in the upper or middle zones are always low likelihood ratio, whereas if the defect/opacity is in the lower zones, these patients are assigned intermediate likelihood ratio. For example, a V / Q scan in a patient with a lower lobe infiltrate would not be helpful in ruling out a PE but would make the decision to anticoagulate easier if it came back with a high likelihood ratio interpretation. Nonsegmental defects, regardless of ventilation or chest x-ray findings, are always classified as low likelihood ratio. In patients with a variety of perfusion defects, the criteria with the highest likelihood ratio is assigned. High Likelihood Ratio
In the PIOPED study, high probability V / Q scans had a sensitivity of 41%, a specificity of 97'/0, and a positive predictive value of 88% (see
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Fig. 3). What this means is that nearly 60% of patients with PE are not classified into this category. To identify all patients with a PE, it is necessary to pursue this diagnosis in patients in other categories. Patients with the same prior probability of embolism as the PIOPED patients who have a high probability scan have an 88% chance of having a PE. Thus, a high probability result usually signifies a PE. Intermediate Likelihood Ratio
Most scans in the PIOPED study fell into the intermediate category (Fig. 4); however, the specificity was only 55%, the sensitivity was 42%, and the positive predictive value was 30%. An intermediate scintigraphic study result is essentially worthless; it does not change the prior probability of PE. This result is nondiagnostic and should not be an end point in the evaluation for PE. Low Likelihood Ratio
A V/Q scan with a low probability had a sensitivity of 16% and a specificity of 59% (Fig. 5). If presumed negative, the scan still misses PE 16% of the time. A low probability result should not be misinterpreted by the emergency physician as a negative study result. In the proper clinical setting, it is essential to continue to pursue the diagnosis of PE. Very Low Likelihood Ratio
The initial PIOPED criteria included a very low category that was not included in the revised criteria. Unlike the low and intermediate categories, there was a high interobserver agreement for this category. Furthermore, because this category usually can be taken to indicate the absence of PE, many nuclear medicine physicians still use this category. Normal
None of the patients termed normal had a PE. Multiple studies have shown that a normal scan essentially rules out any clinically significant PEs. Clinical Correlation
The assignment of post-test probability should also incorporate the clinician’s pretest clinical probability for PE. This probability should also be broken down into high, intermediate, and low probability. In patients
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Figure 4. Intermediate likelihood ratio scan. A, Posterior-anterior (/eft)and lateral (right) chest radiograph shows a pleural based density at the right base (Hampton’s hump). 13,A small defect at the base of the right lung (arrowheads). Compare the sharp costophrenic angle of the left lung on the LPO view with the defect in the right lung seen on the RPO view. Note the importance of the chest radiograph. The defect on the lung scan is small; however, it corresponds to the chest radiograph finding which represents a collapsed posterior basilar segment of the right lower lobe. Pulmonary angiography was positive in this patient. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique.
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Figure 5. Low likelihood ratio scan. The six-view perfusion scan is shown on the left. There are irregularly shaped defects in both lungs that do not correspond to the segmental anatomy of the lung. On the right, perfusion and the single breath from the ventilation scan are shown in the left posterior oblique projection. The pattern of ventilation is matched to the pattern of perfusion, a ventilationlperfusion match. Combined with a normal chest radiograph this ventilation/perfusionscan has a low likelihood ratio for recent pulmonary embolism. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique.
with a high clinical probability, a high likelihood ratio V/Q scan raises the PPV from 88% to 96%. Intermediate clinical likelihood with a high likelihood ratio scan has a PPV of 88%, similar to the value of the scan itself. An intermediate V/Q scan does not change the clinical likelihood of disease; however, a low likelihood ratio V/Q scan combined with a low clinical likelihood changes the negative predictive value to 96%. Thus, this combination significantly decreases the probability of PE. The clinical impression does not change the predictive values of a normal perfusion scan. These important results from the PIOPED study used the assignment of pretest clinical probability for PE based on the judgment of individual physician investigators and were not based on an objective set of criteria. OPTIMIZING INTERPRETATION
The agreement between readers in the PIOPED study was excellent for high probability (95%), very low probability (92%),and normal scans (94%), but was only 75% and 70% for intermediate and low probability scans, respectively. The nuclear medicine scans in the PIOPED study were read by very experienced readers in large academic centers and still had a 25% discordance for the category in which most patients’
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scans were assigned. In contrast, agreement among angiogram readers was excellent for the presence of PE (92%).For patients without PE, the inter-reader agreement was slightly lower (83%).In many centers, V/Q scans are read initially by residents or radiologists with limited experience in pulmonary scintigraphy. The value of an experienced reader also has been studied and is shown to be more accurate than the PIOPED criteria. Called the gestalt or overall pattern interpretation, this can be used as an adjunct to the specific PIOPED classifications. BEDSIDE SCANNING AND PERFUSION SCANS ONLY
The ability exists to perform bedside V/Q scanning by using a portable gamma camera and substituting Xe133with another gas or aerosol that does not require a special room, or by just performing a perfusion scan. This study can be used to assign probability in patients who are unstable and should not be transported. Jolliet et a1 showed favorable results in their study of 45 ICU patients, most of whom had a high clinical probability of PE.3 Many centers do not have access to this technology at this time. Although some investigators have had good success using perfusion scans only: ventilation scan helps to identify the cause of perfusion defects, and therefore most investigators recommend perfusion and ventilation scans. SUMMARY
V/Q imaging is often very useful in evaluating patients in whom a PE is suspected. A normal scan result can be used to exclude embolism and a high likelihood ratio scan can be used to make the diagnosis of PE. Most patients with PE do not have high likelihood ratio scans; therefore, it is important to pursue this diagnosis in patients with intermediate likelihood ratio scans and in the appropriate clinical setting for patients with the low likelihood ratio scans. In patients with parenchymal chest x-ray abnormalities who are likely to fall into the intermediate category, it can be more appropriate to use CT angiography instead of V/Q scintigraphy. This strategy probably increases the fraction of scans with high diagnostic utility. References 1. Biello DR, Mattar AG, McKnight RC, et al: Ventilation-perfusion studies in suspected pulmonary embolism. AJR Am J Roentgen01 133:1033-1037, 1979 2. Gottschalk A, Sostman HD, Juni JE, et al: Ventilation-perfusion scintigraphy in the PIOPED Study: 11. Evaluation of criteria and interpretations. J Nucl Med 3411191126, 1993 3. Jolliet P, Slosman DO, Ricou B, et al: Pulmonary scintigraphy at the bedside in intensive care patients with suspected pulmonary embolism. Intens Care Med 21:723-728, 1995
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4. Kahn D, Bushnell DL, Dean R, et al: Clinical outcome of patients with a “low probability” of pulmonary embolism on ventilation-perfusion lung scan. Arch Intern Med 149:377-379, 1989 5. h i p p i n g HW, Bolt W, Venrath H, et al: Eine neue methode zur prufung der herzund lungenfunktion: Die regionale funktionsanalyse in der lungen- und herzklinik mit hilfe des radioactiven edelgases Xenon-133. Dtsch Med Wochenschr 80:1146, 1955 6. Lee ME, Biello DR, Kumar 8, et al: ”Low-probability” ventilation-perfusion scintigrams: Clinical outcomes in 99 patients. Radiology 156:497-500, 1985 7. McNeil BJ, Holman L, Adelstein J: The scintigraphic definition of pulmonary embolism. JAMA 227753-756, 1974 8. Miniati M, Pistolesi M, Marini C, et al: Value of perfusion lung scan in the diagnosis of pulmonary embolism: Results of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Am J Respir Crit Care Med 154:13871393, 1996 8a. Parker JA, Coleman RE, Siege1 BA, et al: Procedure guideline for lung scintigraphy: 1.0. J Nucl Med 371906-1910,1996 9. The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 26312753-2759, 1990 10. Smith R, Maher JM, Miller RI, et al: Clinical outcomes of patients with suspected pulmonary embolism and low-probability aerosol-perfusion- scintigrams. Radiology 1641731-733, 1987 11. Taplin GV, Johnson DE, Dore EK, et al: Suspension of radioalbumin aggregates for photoscanning the liver, spleen, lung and other organs. J Nucl Med 5:259-275, 1964 12. Wagner HN, Sabiston DC, Iio M, et al: Regional pulmonary blood flow in man by radioisotope scanning. JAMA 187601, 1964 13. Wagner HN, Sabiston DC, MaAfee JG et al: Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Engl J Med 271:377, 1964
Address reprint requests to J. Anthony Parker, MD, PhD Division of Nuclear Medicine Department of Radiology Beth Israel Deaconess Medical Center Boston, MA 02215-5491 e-mail: [email protected]
0733-8627/01 $15.00
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VENTILATION/PERFUSION SCINTIGRAPHY Alan M. Kumar, MD, and J. Anthony Parker, MD, PhD
Lung scintigraphy does not primarily image pulmonary emboli (PE) but rather images the physiologic effects of PE on regional ventilation and perfusion. When a PE obstructs pulmonary blood flow to a region of the lung, the ventilation to this region usually remains normal, giving a ventilation/perfusion (V/Q) mismatch. Regions of the lung with decreased ventilation because of airway disease have reflex vasoconstriction, to prevent shunting of unoxygenated blood to the systemic circulation, giving a V/Q match. The region of altered physiology is much larger than the embolus itself and thus is easily visualized using the relatively low resolution of scintigraphy. Furthermore, evaluation of the altered physiology can provide useful information about the severity of the process. Lung scintigraphy is not always able to identify uniquely the pathologic process from evaluation of the physiologic effects of the process, however. For example, regions where the chest x-ray, perfusion scan, and ventilation scan are all abnormal (sometimes called a triple match) can be due to either a primary pulmonary process or to an embolus with infarction. After describing the relevant lung physiology, this article explains how the findings on lung scintigraphy are interpreted and used to provide information about the diagnosis of PE. HISTORY
The first nuclear medicine studies of the lung used radioactive gas to assess regional ventilation in lung ~ a n c e r Taplin .~ et a1 developed From the Harvard Affiliated Emergency Medicine Residency, Department of Emergency Medicine, Brigham and Women’s Hospital (AMK); and Division of Nuclear Medicine, Department of Radiology, Beth Israel Deaconess Medical Center (JAP), Boston, Massachusetts
EMERGENCY MEDICINE CLINICS OF NORTH AMERICA VOLUME 19 * NUMBER 4 NOVEMBER 2001
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macroaggregated albumin particles labeled with I'31 to measure regional pulmonary blood flow, and Wagner et a1 applied perfusion scanning to the diagnosis of PE.2-3Simultaneous evaluation of perfusion and ventilation by radioactive gas and subsequently by radioactive aerosol was used to increase the specificity of the diagnosis of PE.I3The size, multiplicity, character, and correspondence of defects on perfusion scan, ventilation scan, and chest x-ray were combined into diagnostic schemes by McNeil et al, Biello et al, and the PIOPED investigators.', 7, Most comparisons of lung scintigraphy and pulmonary angiography have suffered from referral bias owing to the small fraction of patients who go on to pulmonary angiography after lung scan. Because of the high rate of arteriography, the authors' focus here is on reviewing the results of the PIOPED study for the comparison of lung scintigraphy and pulmonary arteriography.
ANATOMY AND PHYSIOLOGY
The airways display a branching pattern from the trachea down to the terminal respiratory units or alveoli. The typical adult has about 250 to 300 million alveoli, each with an average diameter of 150 pm. Although the direct anatomic pathway is the most common route of air to the alveoli, alternative routes such as the pores of Cohn (between neighboring alveoli), and the canals of Lambert (between bronchioles and alveoli) are sometimes used to prevent the collapse of an obstructed segment. The trachea divides into the right and left mainstem bronchi. The right mainstem subdivides into the right upper, middle, and lower lobe bronchi. The left mainstem subdivides into the left upper and lower lobe bronchi. Each lobe is divided further into segments, eighteen in all (Fig. 1). The main vascular supply to the lungs, the pulmonary arteries, divide in a branching pattern similar to the airways following the bronchi to the level of the alveoli. The capillaries surrounding each alveolus have an average diameter of 7 to 10 pm. The arterial blood supply to the lungs is from two to four bronchial arteries, originating from the aorta. They anastomose with the pulmonary circulation at the capillary level. Ventilation and perfusion are both significantly affected by gravity and patient position. In the upright position, the apices receive one half of the perfusion of the bases. In the supine position, there is more of an equal distribution of blood flow. There is an increased relative flow to the dependent portions of the lungs, however. Because of gravity, the upper zones of the lungs have greater negative intrapleural pressure. This supplies more tethering support to the alveoli in that region, and they tend to remain open during expiration. Conversely, the alveoli in the lower lung zones are more likely to collapse and open during the alternating phases of respiration. Because of the increased change in potential volume at the lower zones, gas exchange is much greater at
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Figure 1. Segmental anatomy of the lung. Left upper lobe: A-1 , posterior apical segment; A-2, anterior segment; A-3, superior lingular segment; A-4, inferior lingular segment. Left lower lobe: B-1, superior segment; 8-2, anteromedial segment; B-3, lateral basal segment; 8-4, posterior basal segment. Righf upper lobe: C-1, apical segment; C-2, posterior segment; C-3, anterior segment. Right middle lobe: D-1, lateral segment; D-2, medial segment. Right lower lobe: E-1, superior segment; E-2, posterior basal segment; E-3, lateral basal segment; E-4, anterior basal segment. (From Rosen P [edl: Emergency Medicine: Concepts 2, ed 4. St Louis, MO, Mosby, 1998; with permission.) and Clinical Practice, VOI
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the bases. In a healthy adult patient, ventilation at the base is 150% of that at the apex. Ventilation and capillary perfusion should match for efficient gas exchange. Autoregulatory mechanisms exist in the lungs to cause local vasoconstriction is areas of hypoventilation, resulting in redistribution of blood flow away from that area. When there is local ischemia, however, ventilation rarely changes. In humans, bronchoconstriction and shifting of ventilation away from the ischemic region is transient and uncommonly seen. Patients with a PE should have normal ventilation scans, barring secondary complications. PERFUSION IMAGING
Perfusion imaging is based on the principle of capillary blockade. Virtually all perfusion studies are performed using T~~~~-macroaggrein diameter gated albumin (Tc99m MAA), a particle usually 10 to 9 0 ~ m with a 6-hour physical half-life and a 2 to 9 hour biologic half-life. It is prepared by denaturing human serum albumin. The radiopharmaceutical is injected intravenously and mixes uniformly with venous blood by the time it reaches the right heart. Many tracer particles are larger than the capillaries in the lung and lodge in the precapillary arterioles. Fewer than 0.1% of the capillaries are usually blocked. The distribution of tracer usually correlates to the various pulmonary segments. Images are collected in up to eight positions (i.e., anterior, posterior, right and left lateral, right anterior and posterior oblique, and left anterior and posterior oblique) on a large field of view gamma camera. The best images are obtained in the upright position, where the lungs are most expanded and there is the least diaphragmatic motion. Segments with defects in perfusion create images with corresponding areas of decreased tracer uptake. This process mimics that of pulmonary embolization but can also be caused by other conditions such as pneumonia, effusion, and bullae. VENTILATION IMAGING
Unlike perfusion imaging, there are a few choices of ventilation radiopharmaceutical agents. One commonly used is Xe133,which is an inert gas with a 5.2-day physical half-life and a 1-minute biologic halflife. It circulates into the lung through normal ventilation similar to room air. The distribution of Xe133after a single breath shows lung ventilation. The number of counts that can be collected during a single breath is low, however, so the images are of relatively low resolution. Exhaled radioactive Xe133gas can be trapped using an activated charcoal filter, but some gas can leak into the room, particularly with sick patients. Ventilation studies must be performed in negative-pressure rooms and with the exhaust placed low in the room to capture the gas, which is heavier than air.
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Advantages to Xe133include price, easy availability, and the ability to perform inspiration, equilibrium, and wash-out phases. The singlebreath image is more sensitive, for large regions of mild to moderately reduced ventilation, and the wash-out images are more sensitive, for smaller regions of markedly reduced ventilation. Using all three phases provides the most sensitive ventilation study for evaluation of airway disease. XelZ7,which is similar to Xe133,has more favorable imaging characteristics, but because of higher cost of production, it is not commercially available. Because of the very short half-life of Krsl (13 seconds) it decays before coming to equilibrium. Good-quality images can be collected during tidal breathing with an isotope distribution similar to a single breath image. KrS1does not allow equilibrium or wash-out phases and, like XelZ7,has limited availability. The ventilation study is performed in the posterior projection to cut down on artifact created from soft tissues and to maximize the number of pulmonary segments seen. During wash-out, posterior oblique images are also obtained. In a typical Xe133ventilation scan, the patient is fitted with an airtight mask and run through the three phases previously mentioned. An initial deep inspiration phase has the patient take as deep a breath as possible and hold while the camera collects the image. The second phase has the patient breathing an air-Xe133mixture for 3 to 5 minutes in a closed system to collect an equilibrium image. The final phase involves providing fresh air to the patient to "wash-out" the xenon gas and obtain images to evaluate for gas trapping, an indication of obstructive lung disease. This test requires extensive patient cooperation and participation, which can limit the ability to perform a quality study. Technetium-labeled aerosols also can be used to image ventilation. They are similar to Krs1 in that they do not allow for wash-out images or dynamic single-breath imaging. Because T c ~ ~is" used for both the aerosol and the MAA, using a lower dose for the first procedure and a higher dose for the second procedure reduces the interference between images. Technetium-labeled aerosols are easier to prepare, administer, and image. There is no special venting required after Tc is used, and it can be used portably if necessary. Patient cooperation for special breathing is unnecessary, allowing a simpler method of administration. CLINICAL APPLICATIONS The indications for ordering a V/Q scan are limited. The most common reason is to assess for the probability of PE in a patient with clinical symptoms. It can also be ordered to assess for PE in patients without clinical symptoms of a blood clot in the lungs, but with a newly documented deep vein thrombosis (DVT) and for whom a positive V/ Q scan would change the management. It can also be performed just prior to resolution of anticoagulation therapy to have a new baseline of comparison if the patient were to have new symptoms. V/Q scans can
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also be used to assess lung function prior to resection for lung cancer, prior to lung volume reduction surgery, or after transplantation. Tc99m MAA scanning can be used to assess right-to-left shunts. In the emergency department (ED) the assessment of probability of a PE is the most common reason to order a V/Q scan. In a patient with a clear chest radiograph, the V/Q scan is the study of choice for evaluation of PE embolism because it is noninvasive and carries a minimal risk of complications. When chest x-ray findings make it likely that the lung scan will not provide a clear answer, many clinicians choose CT angiography as the first choice (see elsewhere in this issue). Although there are no absolute contraindications to performing a V/Q scan, the study is not completely without risk, and there are certain relative contraindications that must be considered before proceeding. Tc99m MAA has a short half-life and fragments before leaving the lungs, being removed from the circulation by the reticuloendothelial system. In patients with right-to-left shunts, a large number of unfragmented particles can enter the systemic circulation. There have been no documented adverse effects from systemic MAA particles, and MAA has been used to evaluate right-to-left shunts, but theoretically, they could cause adverse effects on the cerebral and coronary circulation. In patients with severe pulmonary hypertension, the Tc99mMAA molecule's obstruction of preterminal arterioles has been reported to exacerbate the condition acutely and lead to complications. Also, care should be taken in patients with documented hypersensitivity to human serum albumin, a building block for T c ~ ~MAA. " In pregnant patients, the administered activity can be reduced if the patient can tolerate a somewhat longer procedure. The radiation dose to the fetus is small, and the risk-to-benefit ratio is low for indicated studies. When one requests a V/Q scan, the radiologist interpreting the study needs certain information. The radiologist should be considered a consultant who will interpret the study based on the particular patient being presented. The emergency physician should convey the clinical history, noting symptoms of chest pain, dyspnea, hemoptysis, and syncope, and discuss abnormal vital signs. Age, risk factors for PE, as well as symptoms or a known recent diagnosis of DVT should be presented. Previous medical history, especially that which could affect the V/Q scan images and interpretation, such as prior PE, congestive heart failure, chronic obstructive pulmonary disease, radiation therapy, or asthma, should also be conveyed. A chest x-ray should be obtained in every patient prior to proceeding to V/Q scan, because it can sometimes change the differential diagnosis. It is also an essential component in the proper interpretation of the V/Q scan. The plain radiograph should have been performed within the past 12 to 24 hours to better define the spatial characterization of the lungs before the V/Q scan can produce a functional assessment with which to compare it. Any other recent studies, such as compression ultrasonography of the lower extremities or a CT angiogram, also should be discussed with the consulting radiologist.
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V/Q INTERPRETATION Normal Scans
A normal perfusion scan is shown in Figure 2. There is normally a gradient from the apex to the base that is caused by the increased perfusion at the base. There is an obvious defect created by the cardiac silhouette and aortic knob in the anterior image, although they are noticeable in multiple other images as well. The lateral images, and to a lesser degree, the oblique images, have overlap between the lungs. Up to one third of the scintigraphic image can come from the superimposed lung, thereby obscuring significant perfusion defects seen in other views. Subtle abnormalities unrelated to the lung parenchyma can cause defects in an otherwise normal perfusion scan. Cardiomegaly, tortuosity of the aorta, and mediastinal or hilar prominence can cause defects along the medial border of the lung. Small pleural effusions can blunt the posterior sulci or create a linear defect along the region of the major fissure, termed the fissure sign. Moderately sized effusions occasionally can mimic segmental defects. Incidental segmental and subsegmental defects can be seen in up to 7% of healthy young asymptomatic people, and that percentage rises in smokers. There is no way to be certain of the cause of these seemingly benign defects, because on occasion multiple small emboli have been documented to simulate these conditions on scintigraphic images. A normal ventilation scan is shown in Figure 3. After the initial inspiratory phase, a relatively homogenous distribution of radiotracer
Figure 2. Normal perfusion scan. A cardiac impression on the anterior views. There is a gradient in intensity from apex to base and from anterior to posterior. There is a slight decrease in activity over the hilar regions due to region occupied by the bronchi and vessels. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique.
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Figure 3. High likelihood ratio scan. A six-view perfusion scan is shown on top and ventilation scan is shown on bottom. The perfusion scan shows marked abnormalities in both lungs. The only relatively normal perfusion is seen in the anterior and apical posterior segments of the left upper lobe. There is some perfusion in the right lung; however, in comparison to the left upper lobe it can be seen that there is markedly decreased perfusion throughout the entire right lung. The ventilation study in the posterior projection is normal. The initial breath image that represents ventilation should be compared to the posterior view on the perfusion scan. The initial breath image is followed by several equilibrium images. The last row shows wash-out and finally a delayed trapping image. Note that this ventilation study was performed after the perfusion and there is shine through of the perfusion activity in the ventilation images, most clearly seen on the delayed trapping image. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique, IB = initial breath, Eq = start of equilibrium, WO = start of wash-out, Trap = trapping image.
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occurs. The equilibrium phase image should match the inspiratory image in normal patients, although the inspiratory phase has less activity. The wash-out images should show clearance of the gas, usually within 3 minutes. Wash-out is the most sensitive phase for the detection of trapping. Retention of xenon is indicative of obstructive disease. Xenon gas is also soluble in fatty tissue and, to a lesser degree, blood. Images taken in the posterior position minimize artifact from breast tissue. A seeming abnormality at the base of the right lung can sometimes be due to fatty liver with increased activity. Air swallowing, especially in pediatric patients, can also produce activity in the stomach that projects onto the collected images. Ventilation images usually are obtained first to prevent background activity from the perfusion study when one is using Xe133.An advantage of XelZ7and Krsl is the ability to do postperfusion images, which allows one to choose the projection to collect ventilation images that best evaluate a defect in a particular region or segment during the preceding perfusion scan. Abnormal Scan Result
An abnormal scan result is defined as either a ventilation or perfusion study that has focal areas of defect or inhomogeneity of radiopharmaceutical distribution. Clinically significant PEs cause obstruction of arterial blood flow to an affected lobe segment, or less commonly, subsegment. When a patient undergoes a V/Q scan, the T c ~ ~ MAA " distributes evenly throughout the capillaries except in the obstructed segment, where the clot prevents downstream passage of the radiotracer, resulting in a segmental defect on a perfusion scan. The abnormal blood in the affected segment does not alter the regional ventilation; therefore, the ventilation images collected should remain unaffected. This disassociation between a typically wedge-shaped perfusion defect corresponding to a pulmonary segment with preserved ventilation leads to the classic manifestation of pulmonary embolus: the segmental V/Q mismatch. Focal areas of deficit on a perfusion scan can be caused by myriad conditions: PE Pneumonia Pulmonary edema Pleural effusion Radiation therapy Atelectasis Vasculitis Primary tumor or metastasis Pulmonary fibrosis Localized hypoxia secondary to asthma, bronchitis, or emphysema Perfusion defects are categorized as segmental or nonsegmental, depending on whether they correspond to a known bronchopulmonary
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anatomic segment. Nonsegmental defects do not correspond to known anatomic segments and are usually not wedge shaped. Possible causes of nonsegmental defects significantly overlap those of segmental defects. Classically, PEs are segmental, so that the ability to differentiate between the two is crucial in assigning a likelihood ratio. Pulmonary embolic defects extend to the periphery of the lung, whereas many other pulmonary processes can spare the periphery. Perfusion at the periphery of a defect, called a stripe sign, suggests a nonembolic cause. The shape, location, and size of the defect should be compared in multiple views of the scan to see if it fits with a known anatomic segment. Size is classified further into small (<25% of the segment), moderate (25%75%), or large (>75%). The size and number of defects are used within a set of interpretation criteria to assess the probability of the abnormalities representing a PE. In the PIOPED criteria, large defects are counted as 1 segmental equivalent; moderate defects are counted as 0.5 segmental equivalents; and small defects are not counted. The location of the defect in relation to the upper, middle, or lower zones of the lungs also play a role in the rite ria.^ The perfusion scan is also compared to the ventilation scan, and vice versa. Any perfusion defect should be compared to the corresponding region on the ventilation scan (see Fig. 3). A mismatch exists if there is a normal xenon image. A match exists if there is a ventilation abnormality in the same region. Although a mismatch is the key interpretive finding, the size, number, and location of defects have a role in the interpretive schema. The V/Q-matched defect should also be compared specifically to the chest x-ray to see if the radiograph also shows a matching abnormality. This occurrence is called a triple match. A triple match can be caused by a primary parenchymal process, leading to decreased ventilation and secondarily decreased perfusion. A PE with infarction has primarily decreased perfusion with secondary air space filling and decreased ventilation, but the result is also a triple match. V/Q INTERPRETIVE CRITERIA
The radiologist’s reading of a V/Q scan is based on a set of interpretive criteria that assigns a likelihood ratio for the scintigraphic findings. The likelihood ratio is combined with the prior probability of PE to produce a posterior probability. Scans are defined as falling into one of five major criteria: normal, very low, low, intermediate, and high likelihood ratio for PE. Traditionally, the word probability has been used for scan results (e.g. high probability scan). When describing the results of the PIOPED study the authors follow this conventional usage; elsewhere, they follow the recommendation of the Society of Nuclear Medicine Procedure Guideline for Lung Scintigraphysaand use the more accurate term for a test result, likelihood ratio. Given a typical prior probability of disease, a high likelihood ratio scan indicates a greater than 80% poste-
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rior probability of PE. Intermediate scans give a probability of 20% to 8O%, to and low likelihood ratio scans give a probability below 20%. A very low likelihood ratio places the posterior probability at below 5%. When the chest x-ray, perfusion scan, and ventilation scan are all abnormal (a triple match), a PE with secondary infarction cannot be distinguished from any other cause of infiltration. In this case, the lung scan is often called indeterminate for PE. Over time, multiple criteria models were developed and modified, the most common being the modified Biello criteria.' In the late 1980s, a multimillion dollar multicenter trial was undertaken for the prospective investigation of PE diagnosis (PIOPED). PIOPED was designed to compare V/Q scans for acute PE using a predetermined set of interpretive criteria with pulmonary angiography. Over the past 10 years, the PIOPED and the modified PIOPED criteria have become the most widely used interpretive schemes.2, PIOPED was able to study 931 patients who had V/Q scans for acute PE, 755 of whom also went on to have pulmonary angiograms. Of the 176 patients who did not have angiograms, 136 had scan readings of low probability or normal/near normal. In follow-up study, none of these patients were treated with anticoagulation or developed clinically evident PE. Of the 755 patients who did have angiograms, an additional 24 were removed for technical difficulty or inability to interpret the angiogram to a high degree of certainty. Table 1 the results of the remaining patients with V/Q scans and angiograms. The final group of patients was selected from a group of more than 5500 patients in whom a lung scan was requested. Although the study design evaluated every patient for enrollment, the characteristics of the final group still had some selection bias. The 1-year mortality of the final group of patients was very low. Usually, the death rate in a year for a group of patients referred for lung scan is over 10%; most patients dying 6, The prior probability of PE was also of their underlying di~ease.~, higher than in most hospitals. At the Beth Israel Deaconess Medical Center in 1998, the incidence of high or moderately high likelihood ratio readings was 7%; in the PIOPED study, the incidence of high probability scan was 16%. Thus, the PIOPED patients had fewer serious underlying conditions, and they were more likely to have PEs than the average patient. Table 1. RESULTS OF PIOPED STUDY ~~
Scan Result
Angiogram Results Positive for PE
Angiogram Results Negative for PE
High Intermediate Low Normal Totals
102 105 39 5 251
14 217 199 50 480
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The criteria used in PIOPED have been modified since the original study and are listed here: High Probability: >SO% Two or more large mismatched segmental defects without a radiographic abnormality (or the perfusion defect is substantially large than the radiographic abnormality) Any combination of mismatched defects equivalent to the above (two moderate defects, one large defect) Intermediate Probability: 20% to 80% One moderate mismatched segmental defect with a normal radiograph One large and one moderate mismatched segmental defect with a normal radiograph Difficult to categorize as high or low probability Not meeting the stated criteria for high or low probability Low Probability: <20% Nonsegmental perfusion defects Any perfusion defect substantially smaller than a corresponding radiographic abnormality Matched ventilation and perfusion defects with a normal chest radiograph Small subsegmental perfusion defects Normal: No perfusion defects The PIOPED investigators chose to define specific criteria for high and low probability, with all other defects falling into an intermediate category. Only the classic presentation of multiple large and moderate segmental perfusion defects with a normal ventilation scan would qualify as high probability in a patient with a normal chest x-ray. If the perfusion defect is substantially larger than the area of opacity on plain radiography, this also qualifies as high probability. This degree of strictness in assigning the high likelihood category is based on the fact that PEs are multiple in 90% and bilateral in 85% of cases. Perfusion abnormalities in relation to an opacity on chest x-ray in the upper or middle zones are always low likelihood ratio, whereas if the defect/opacity is in the lower zones, these patients are assigned intermediate likelihood ratio. For example, a V / Q scan in a patient with a lower lobe infiltrate would not be helpful in ruling out a PE but would make the decision to anticoagulate easier if it came back with a high likelihood ratio interpretation. Nonsegmental defects, regardless of ventilation or chest x-ray findings, are always classified as low likelihood ratio. In patients with a variety of perfusion defects, the criteria with the highest likelihood ratio is assigned. High Likelihood Ratio
In the PIOPED study, high probability V / Q scans had a sensitivity of 41%, a specificity of 97'/0, and a positive predictive value of 88% (see
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Fig. 3). What this means is that nearly 60% of patients with PE are not classified into this category. To identify all patients with a PE, it is necessary to pursue this diagnosis in patients in other categories. Patients with the same prior probability of embolism as the PIOPED patients who have a high probability scan have an 88% chance of having a PE. Thus, a high probability result usually signifies a PE. Intermediate Likelihood Ratio
Most scans in the PIOPED study fell into the intermediate category (Fig. 4); however, the specificity was only 55%, the sensitivity was 42%, and the positive predictive value was 30%. An intermediate scintigraphic study result is essentially worthless; it does not change the prior probability of PE. This result is nondiagnostic and should not be an end point in the evaluation for PE. Low Likelihood Ratio
A V/Q scan with a low probability had a sensitivity of 16% and a specificity of 59% (Fig. 5). If presumed negative, the scan still misses PE 16% of the time. A low probability result should not be misinterpreted by the emergency physician as a negative study result. In the proper clinical setting, it is essential to continue to pursue the diagnosis of PE. Very Low Likelihood Ratio
The initial PIOPED criteria included a very low category that was not included in the revised criteria. Unlike the low and intermediate categories, there was a high interobserver agreement for this category. Furthermore, because this category usually can be taken to indicate the absence of PE, many nuclear medicine physicians still use this category. Normal
None of the patients termed normal had a PE. Multiple studies have shown that a normal scan essentially rules out any clinically significant PEs. Clinical Correlation
The assignment of post-test probability should also incorporate the clinician’s pretest clinical probability for PE. This probability should also be broken down into high, intermediate, and low probability. In patients
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Figure 4. Intermediate likelihood ratio scan. A, Posterior-anterior (/eft)and lateral (right) chest radiograph shows a pleural based density at the right base (Hampton’s hump). 13,A small defect at the base of the right lung (arrowheads). Compare the sharp costophrenic angle of the left lung on the LPO view with the defect in the right lung seen on the RPO view. Note the importance of the chest radiograph. The defect on the lung scan is small; however, it corresponds to the chest radiograph finding which represents a collapsed posterior basilar segment of the right lower lobe. Pulmonary angiography was positive in this patient. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique.
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Figure 5. Low likelihood ratio scan. The six-view perfusion scan is shown on the left. There are irregularly shaped defects in both lungs that do not correspond to the segmental anatomy of the lung. On the right, perfusion and the single breath from the ventilation scan are shown in the left posterior oblique projection. The pattern of ventilation is matched to the pattern of perfusion, a ventilationlperfusion match. Combined with a normal chest radiograph this ventilation/perfusionscan has a low likelihood ratio for recent pulmonary embolism. RAO = right anterior oblique, Ant = anterior, LAO = left anterior oblique, LPO = left posterior oblique, Post = posterior, RPO = right posterior oblique.
with a high clinical probability, a high likelihood ratio V/Q scan raises the PPV from 88% to 96%. Intermediate clinical likelihood with a high likelihood ratio scan has a PPV of 88%, similar to the value of the scan itself. An intermediate V/Q scan does not change the clinical likelihood of disease; however, a low likelihood ratio V/Q scan combined with a low clinical likelihood changes the negative predictive value to 96%. Thus, this combination significantly decreases the probability of PE. The clinical impression does not change the predictive values of a normal perfusion scan. These important results from the PIOPED study used the assignment of pretest clinical probability for PE based on the judgment of individual physician investigators and were not based on an objective set of criteria. OPTIMIZING INTERPRETATION
The agreement between readers in the PIOPED study was excellent for high probability (95%), very low probability (92%),and normal scans (94%), but was only 75% and 70% for intermediate and low probability scans, respectively. The nuclear medicine scans in the PIOPED study were read by very experienced readers in large academic centers and still had a 25% discordance for the category in which most patients’
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scans were assigned. In contrast, agreement among angiogram readers was excellent for the presence of PE (92%).For patients without PE, the inter-reader agreement was slightly lower (83%).In many centers, V/Q scans are read initially by residents or radiologists with limited experience in pulmonary scintigraphy. The value of an experienced reader also has been studied and is shown to be more accurate than the PIOPED criteria. Called the gestalt or overall pattern interpretation, this can be used as an adjunct to the specific PIOPED classifications. BEDSIDE SCANNING AND PERFUSION SCANS ONLY
The ability exists to perform bedside V/Q scanning by using a portable gamma camera and substituting Xe133with another gas or aerosol that does not require a special room, or by just performing a perfusion scan. This study can be used to assign probability in patients who are unstable and should not be transported. Jolliet et a1 showed favorable results in their study of 45 ICU patients, most of whom had a high clinical probability of PE.3 Many centers do not have access to this technology at this time. Although some investigators have had good success using perfusion scans only: ventilation scan helps to identify the cause of perfusion defects, and therefore most investigators recommend perfusion and ventilation scans. SUMMARY
V/Q imaging is often very useful in evaluating patients in whom a PE is suspected. A normal scan result can be used to exclude embolism and a high likelihood ratio scan can be used to make the diagnosis of PE. Most patients with PE do not have high likelihood ratio scans; therefore, it is important to pursue this diagnosis in patients with intermediate likelihood ratio scans and in the appropriate clinical setting for patients with the low likelihood ratio scans. In patients with parenchymal chest x-ray abnormalities who are likely to fall into the intermediate category, it can be more appropriate to use CT angiography instead of V/Q scintigraphy. This strategy probably increases the fraction of scans with high diagnostic utility. References 1. Biello DR, Mattar AG, McKnight RC, et al: Ventilation-perfusion studies in suspected pulmonary embolism. AJR Am J Roentgen01 133:1033-1037, 1979 2. Gottschalk A, Sostman HD, Juni JE, et al: Ventilation-perfusion scintigraphy in the PIOPED Study: 11. Evaluation of criteria and interpretations. J Nucl Med 3411191126, 1993 3. Jolliet P, Slosman DO, Ricou B, et al: Pulmonary scintigraphy at the bedside in intensive care patients with suspected pulmonary embolism. Intens Care Med 21:723-728, 1995
VENTILATION/PERFUSION SCINTIGRAPHY
973
4. Kahn D, Bushnell DL, Dean R, et al: Clinical outcome of patients with a “low probability” of pulmonary embolism on ventilation-perfusion lung scan. Arch Intern Med 149:377-379, 1989 5. h i p p i n g HW, Bolt W, Venrath H, et al: Eine neue methode zur prufung der herzund lungenfunktion: Die regionale funktionsanalyse in der lungen- und herzklinik mit hilfe des radioactiven edelgases Xenon-133. Dtsch Med Wochenschr 80:1146, 1955 6. Lee ME, Biello DR, Kumar 8, et al: ”Low-probability” ventilation-perfusion scintigrams: Clinical outcomes in 99 patients. Radiology 156:497-500, 1985 7. McNeil BJ, Holman L, Adelstein J: The scintigraphic definition of pulmonary embolism. JAMA 227753-756, 1974 8. Miniati M, Pistolesi M, Marini C, et al: Value of perfusion lung scan in the diagnosis of pulmonary embolism: Results of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Am J Respir Crit Care Med 154:13871393, 1996 8a. Parker JA, Coleman RE, Siege1 BA, et al: Procedure guideline for lung scintigraphy: 1.0. J Nucl Med 371906-1910,1996 9. The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 26312753-2759, 1990 10. Smith R, Maher JM, Miller RI, et al: Clinical outcomes of patients with suspected pulmonary embolism and low-probability aerosol-perfusion- scintigrams. Radiology 1641731-733, 1987 11. Taplin GV, Johnson DE, Dore EK, et al: Suspension of radioalbumin aggregates for photoscanning the liver, spleen, lung and other organs. J Nucl Med 5:259-275, 1964 12. Wagner HN, Sabiston DC, Iio M, et al: Regional pulmonary blood flow in man by radioisotope scanning. JAMA 187601, 1964 13. Wagner HN, Sabiston DC, MaAfee JG et al: Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Engl J Med 271:377, 1964
Address reprint requests to J. Anthony Parker, MD, PhD Division of Nuclear Medicine Department of Radiology Beth Israel Deaconess Medical Center Boston, MA 02215-5491 e-mail: [email protected]