PrEdictive value of coMbined pre-test proBability and blOod gas anaLysis In pulmonary emboliSM—the EMBOLISM study

The clinical diagnosis of pulmonary embolism (PE) remains challenging. Current guidelines of the European Society of Cardiology (ESC) recommend the assessment of clinical pre-test probability (PTP) in hemodynamic stable patients with suspected PE [1]. The most frequently applied prediction rules are the Wells score for PE and the revised Geneva score. Accordingly, PE can be expected in approximately 12% in the “PE unlikely” category and 30% in the “PE likely” category, when the two-level classification is used [2]. In the “PE unlikely” category the subsequent laboratory testing for D-dimer is recommended and of major clinical importance. Normal D-dimer (< 0.5 mg/L) and/or negative age-adjusted D-dimer (age × 0.01 mg/L for patients older than 50 years) in the “PE unlikely” group safely rule out PE and effectively reduce unnecessary chest imaging [3‐5].

Due to the low specificity of D-dimer, a positive D-dimer test in patients with a low PTP for PE is the major trigger for over testing with computed tomography pulmonary angiography (CTPA) [6]. Hence, even when adhering to the recommended algorithm, a low PTP and positive D-Dimer testing results in negative CTPA in up to 95% [7‐10]. A viable approach to reduce the overuse of chest imaging via CTPA is the correction of the D-dimer cut-off. As investigated in the recent YEARS and PEGeD study, a D-dimer cut-off of less than 1.0 mg/L is safely applicable in the low-risk category [11, 12] and the usage of both scores resulted in a significant reduction of chest imaging by CTPA.

Next to assessment of PTP and, if necessary, D-dimer testing, capillary blood gas analysis (BGA) is regularly performed in patients with suspected PE. Commonly, hypoxemia and hypocapnia can be found in patients with PE [1]. Despite the pathophysiological plausibility of these findings, so far, no study was able to demonstrate an additional benefit of BGA testing to rule out PE [13, 14].

The aim of the present study was to reevaluate the role of BGA testing and its diagnostic benefits in patients with suspected PE, especially in patients with a low PTP. Using the standardized arterial oxygen tension (PaO2stand), we accounted for hyperventilation and hypocapnia, since both conditions affect the arterial oxygen tension (PaO2) [15] and are frequently seen in patients with PE [1]. In a novel approach, we combined the PTP and D-dimer with BGA results to reduce the need for unnecessary chest imaging in patients with suspected PE. We therefore analyzed the data of patients with suspected PE who were admitted at the emergency department (ED) of a large tertiary care university hospital and received chest imaging by CTPA.

To the best of our knowledge, this is the first investigation to demonstrate an additive value of BGA to reduce the number of unnecessary CTPA examinations in patients with suspected PE. In this retrospective study with a well-defined cohort of patients with suspected PE and subsequent CTPA, standardized PaO2 represents a useful tool to reduce unnecessary chest imaging in patients with low PTP. In the subgroup with a low PTP (Wells score ≤ 4 points), a standardized PaO2 of > 65 mmHg enabled us to increase the D-dimer threshold to < 1.5 mg/L to safely exclude PE. By application of our novel algorithm, a reduction in CTPA rate by approximately 32% could be achieved, without missing a single patient with PE, when age-adjusted D-dimer is considered the gold standard. The particular strength of this novel algorithm is that it is based on two components that are well known and frequently used in clinical practice. Furthermore, even when compared to the recently published PEGeD algorithm [12], the application of our novel algorithm using BGA parameters and a higher D-dimer cut-off levels in patients with low PTP the number of unnecessary CTPA can be reduced by 9.3% without missing a patient with PE. Our novel diagnostic algorithm should be applied to patients in the emergency department when pulmonary embolism is clinically suspected.

Current guidelines recommend the assessment of PE probability in hemodynamic stable patients by the Wells or revised Geneva score with subsequent D-dimer testing and CTPA, if necessary [1]. Therefore, the indication whether to perform CTPA or not in the “PE unlikely” group depends on D-dimer testing. Testing for D-dimer has a poor specificity for venous thromboembolism and elevated D-dimer levels can be found in numerous conditions such as malignant diseases, pregnancy, and infections [18, 19]. Thus, elevated D-dimer levels above 0.5 mg/L are frequent and a leading cause for chest imaging in the “PE unlikely” group. In up to 95% CTPA is negative for PE in this cohort [7‐10, 20]. In 2014, Righini et al. reported that an adjustment of D-dimer levels to the patients’ age (age × 0.01 mg/L for patients older than 50 years) can safely exclude PE. The age-adjusted D-dimer levels increased the exclusion rate of PE from 6.4 to 30% [3] and reduced the unnecessary CTPA, accordingly. To further decrease CTPA frequency in suspected PE, studies then attempted to increase the D-dimer threshold. According to the YEARS algorithm, a D-dimer cut-off of < 1.0 mg/L is appropriate in patients with a low clinical PTP. The application of the YEARS algorithm avoided a total of 14% of CTPA when compared to standard care (Wells score and a fixed D-dimer cut-off of < 0.5 mg/L) [11]. Recently the PEGeD study confirmed the safety of a D-dimer cut-off of < 1.0 mg/L in patients with a low PTP, as assessed by the Wells score (≤ 4 points) [12]. So far, no study successfully investigated higher D-dimer cut-off levels than 1.0 mg/L. Our analysis included patients with suspected PE, clinical PTP as assessed by Wells score, age-adjusted D-dimer levels and CTPA. By adding the standardized PaO2 to a low PTP by Wells score (≤ 4 points) we were able to increase the D-dimer cut-off to < 1.5 mg/L in the “PE unlikely” group.

The diagnostic significance of BGA in the assessment of suspected PE has been controversially discussed in the literature. On the one hand, the assessment of PE probability by the original Geneva score includes blood gas parameters such as the PaO2 and PaCO2 [21]. Furthermore, in patients with malignant disease a benefit of BGA in the diagnosis of PE was recently demonstrated. In this study, the PaO2 was significantly lower in cancer patients and an alveolar-arterial gradient > 20 had 100% sensitivity and negative predictive value [22]. On the other hand, several studies investigating the usage of BGA parameters demonstrated no additional diagnostic benefit. Neither the alveolar–arterial oxygen tension gradient alone, nor a combination with a PaCO2 > 35–36 mmHg and/or the absence of prior thromboembolic disease reached a sensitivity of 100% and were able to increase the PTP in PE [13, 14, 23‐25]. Since its widespread utilization and the common presence of hypoxemia and hypocapnia in patients with PE, BGA, especially the PaO2 and PaCO2, remains a simple bedside tool for clinical evaluation of suspected PE. The aim of the study was to use established standard diagnostics in combination with the BGA to optimize the indication for further chest imaging in the low PTP cohort without missing patients with PE. In our approach, we accounted for the pathophysiological changes commonly observed in PE, i.e., hyperventilation and hypocapnia, by application of the formula proposed by Mays et al. [15]. This correction of PaO2 resulted in a standardized PaO2. The standardized PaO2 is the first BGA parameter to show a sensitivity of 100% in excluding PE in our subgroup of low PTP and D-dimer cut-off < 1.5 mg/L.

The overall prevalence of PE in our registry was 28.2%, which is in accordance with the current literature [26, 27]. While this provides a certain comparability to other studies, it also shows the high proportion of patients with negative CTPA. In fact, there is evidence of an extensive overuse of CTPA in patients with suspected PE due to non-adherence to pre-test scoring algorithms [28, 29]. This aspect must be addressed by strict adherence to pre-test scores and other clinical tools such as D-dimer testing to reduce the number of unnecessary chest imaging and ionizing radiation exposure.

In this large cohort of patients with suspected PE and subsequent CTPA, we were able to show that BGA had an additional benefit to reduce unnecessary chest imaging in patients with low PTP.