Pulmonary Artery

Pulmonary Embolism

Venous thromboembolism (VTE) incorporates deep venous thrombosis (DVT) and PE. VTE is one of the major contributors to global disease burden: the incidence ranges from 100 to 200 per 100,000 persons per year with an increased incidence from 200 to 700 per 100,000 in those ≥70 years. The risk for the disease doubles in each decade after the age of 40 years. PE represents the most serious and potentially life-threatening condition related to VTE. It often occurs as a consequence of DVT when a blood clot breaks off, migrates, and eventually obstructs the pulmonary arteries. An estimation model based on data from six countries of the European Union showed that 317,000 deaths could be attributable to VTE. Approximately one-third of patients suffered from sudden death caused by PE, 59% died as a result of existing but undiagnosed PE, and only 7% of patients who died were appropriately identified with PE. Because the presenting signs and symptoms are nonspecific and overlap in a wide variety of common ailments, diagnosing PE is challenging and relies on a multidimensional prognostic model. Risk stratification of patients into high-risk, intermediate-risk, and low-risk categories is based on the additive value of clinical scores, imaging tests, and laboratory markers. Therefore the current workup typically includes two or more of the following tests: blood assays, computed tomography angiography (CTA) or ventilation/perfusion (V̇/Q̇) scintigraphy, compression venous ultrasonography (CUS) of the deep venous system, and occasionally the reference standard, catheter-based pulmonary angiography. From the resulting array of diagnostic information, the clinician must then assess the patient's likelihood of having PE and initiate treatment. The most extensively used clinical score in acute PE is the pulmonary embolism severity index (PESI) or its simplified version (sPESI), which is helpful in the prognostic assessment of 30-day mortality. For hemodynamically stable patients, pretest probability relies on the revised Geneva score and/or Wells rule, which both aim to stratify patients into three-level (low, intermediate, and high risk) or two-level (PE unlikely and PE likely) schemes based on information that is easy to obtain. Elevated plasma levels of D-dimer as well as markers of myocardial injury (cardiac troponin I or T) and/or ventricular dysfunction (brain natriuretic peptide-BNP and N-terminal-pro BNP) support the diagnosis of PE. However, the relatively low positive predictive values of laboratory biomarkers do not allow reliable exclusion of PE. The suspicion of PE is therefore a common indication for imaging.

CTA is the most used noninvasive imaging method for detection of PE. A negative CTA in patients with low/intermediate risk allows for safely ruling out PE, although in patients with negative CTA, but high probability of PE, further investigations are required. The high spatial resolution of current CT scanners and the administration of contrast media allows for the identification of PE at least to the segmental level. However, potential pitfalls can occur, especially at distal levels of the pulmonary arteries. A retrospective review of PE on CTA showed discordance between subspecialists in chest radiology and general radiologists in 26% of the cases. The disagreement was most frequent if the PE was adjudicated as solitary (46% of solitary PEs were later adjudicated as negative) or segmental/subsegmental (27% of segmental and 59% of subsegmental PE were later considered as negative). Additionally, CTA exposes the patient to ionizing radiation and requires iodinated intravenous contrast, which is potentially nephrotoxic and can provoke allergic reactions. Radiation exposure is of particular concern in young adults and those who are referred for multiple CTA scans because of a history of prior PE.

V̇/Q̇ scintigraphy is a combined noninvasive procedure that uses nuclear radiotracers for diagnosing PE. The reported radiation exposure of the examination is significantly lower compared with CTA (1.1 mSv vs. 4 mSv) and might be a preferred alternative over CTA in younger patients, especially women, in whom radiation exposure of CTA is associated with higher risk of breast cancer. However, V̇/Q̇ scans are frequently nondiagnostic, which raised concerns because of the need for further diagnostic tests. Diagnostic accuracy can be improved by incorporation of a single photon emission tomography (SPECT) to V̇/Q̇ scintigraphy.

Catheter-based pulmonary angiography remains the reference standard technique for the exclusion of PE. The use of this method, however, is infrequent due to the good diagnostic accuracy provided by noninvasive CTA. Furthermore, the invasive nature of the test carries risk for procedure-related complications, especially in patients with hemodynamic instability and/or respiratory failure.

CUS is useful for detection of DVT, which is thought to be a predisposing condition for development of PE. However, a negative test does not exclude the presence of PE: in one study, CUS found DVT in only 30% of patients with proven PE. A proximal DVT detected by CUS in patients with isolated subsegmental PE is an adequate finding to start anticoagulation therapy. However, an ongoing trial raised concerns about treating small blood clots attributed to the elevated risk of bleeding and investigates withholding anticoagulants in patients with subsegmental PE without cancer.

The prognostic value of CMR for diagnosing PE has been investigated in the prospective, multicenter Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) III trial. However, the results were disappointing: CMR images were technically unsatisfactory in 25% of patients. Another study found that 30% of CMR scans were inconclusive. Furthermore, the latter investigation reported high sensitivity for proximal PE (97.7%–100% assessed by two readers) but significantly lower sensitivity for segmental (68%–91.7%) and subsegmental PE (21.4%–33.3%). Another issue is that access to CMR is relatively limited, particularly outside of office hours. Current guidelines therefore do not include CMR in the primary imaging work-up of PE. Nevertheless, because of its radiation-free nature CMR remains a useful imaging modality for detection of PE, especially in young women and children.

There are two fundamental and complementary approaches to CMR in the diagnosis of PE. The earliest approach builds on the model of V̇/Q̇ scintigraphy and uses CE-CMR to evaluate pulmonary perfusion, to identify segmental, wedge-shaped perfusion defects in the pulmonary parenchyma. In this regard, several investigations demonstrated good agreement between CMR lung perfusion and V̇/Q̇ scintigraphy. Another method of diagnosing acute PE on CMR is the visualization of vascular alterations, which include intravascular filling defects, abrupt cutoff of intravascular signal and the absence of contrast material distal to the obstructed artery. Furthermore, CMR allows for accurate evaluation of flow changes in the bronchial arteries in patients with chronic PE.

Molecular CMR with the use of specific contrast agents might also allow for direct visualization of thrombus formation. Fluorine (F) CMR and α2-antiplasmin (α2 ^AP ) labeled contrast agents have been shown to be able to detect thrombi with a diameter <0.8 mm in murine inferior vena cava. Further development of this method in humans might help in the identification of evolving thrombi following invasive procedures with increased risk for thrombosis.

Ferumoxytol is an intravenous iron preparation intended for treatment of the anemia associated with chronic kidney disease. It is a carbohydrate-coated, superparamagnetic iron oxide nanoparticle. Ferumoxytol has been used off-label for CMR as a contrast agent for vascular imaging. It does not contain gadolinium and therefore might be beneficial in patients with renal impairment. The prolonged steady state of ferumoxytol allows T1-weighted CMR to be performed under steady-state conditions (rather than only first-pass imaging with conventional gadolinium contrast agents). Thus ferumoxytol has been proposed to be useful in patients who have difficulty with breath-holding.