Risk Stratification in Acute Normotensive Pulmonary Embolism– Role of Echocardiography Imaging and Biomarkers

Rohit Tandon; Adesh Kumar Singh; Bishav Mohan

doi:10.4103/jiae.jiae_41_21

REVIEW ARTICLE

Year : 2022 | Volume : 6 | Issue : 1 | Page : 45-52

Risk Stratification in Acute Normotensive Pulmonary Embolism– Role of Echocardiography Imaging and Biomarkers

Rohit Tandon, Adesh Kumar Singh, Bishav Mohan
Department of Cardiology, Hero DMC Heart Institute, Ludhiana, Punjab, India

Date of Submission	21-Jul-2021
Date of Acceptance	12-Sep-2021
Date of Web Publication	16-Dec-2021

Correspondence Address:
Dr. Rohit Tandon
Tagore Nagar, Ludhiana - 141 001, Punjab
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiae.jiae_41_21

Abstract

Acute pulmonary embolism (PE) is an important cause of mortality. It requires alertness to facilitate early diagnosis which becomes a benchmark for further risk stratification and optimal management. Although pulmonary artery imaging by computed tomography scan has become the gold standard in diagnosis of acute PE, echocardiography also plays a complementary role as an imaging modality in deciding about the treatment and for prognostication. Combining echocardiography with cardiac-specific biomarker assays further enhances the required diagnostic yield in the emergency setting. In this chapter, we mainly focus on the role of echocardiography along with specific biomarker assays in prognostication of acute PE patients who are normotensive at presentation.

Keywords: Acute pulmonary embolism, biomarkers, echocardiography, risk stratification

How to cite this article:
Tandon R, Singh AK, Mohan B. Risk Stratification in Acute Normotensive Pulmonary Embolism– Role of Echocardiography Imaging and Biomarkers. J Indian Acad Echocardiogr Cardiovasc Imaging 2022;6:45-52

How to cite this URL:
Tandon R, Singh AK, Mohan B. Risk Stratification in Acute Normotensive Pulmonary Embolism– Role of Echocardiography Imaging and Biomarkers. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2022 [cited 2023 Mar 20];6:45-52. Available from: https://jiaecho.org/text.asp?2022/6/1/45/332708

Background and Epidemiology

Acute pulmonary embolism (PE) can be associated with mortality rates in the range of 5%–36%. In-hospital mortality rates in different subsets are as follows:

25%–50% in massive PE which is associated with sustained hypotension (i.e., systolic blood pressure [SBP] <90 mmHg for at least 15 min)
3%–15% in submassive PE which is characterized by elevated cardiac biomarkers for myocardial necrosis (troponins) and/or right ventricular (RV) systolic dysfunction with SBP more than 90 mmHg at presentation
<5% in low risk/nonmassive PE characterized by the absence of hypotension, RV dysfunction, and myocardial necrosis.^[1]

Rapid and accurate risk stratification depends upon assessment of thrombus location and burden and its effects on systemic, pulmonary, and RV hemodynamics.

Initial Risk Stratification

Pathophysiologically, acute PE results in a cascade of events leading to release of neurohormonal factors which cause a rise in pulmonary artery pressures, thereby affecting effective forward cardiac output resulting in hemodynamic decompensation and eventually cardiogenic shock. In patients presenting in shock, termed as massive PE, urgent clot removal from the main pulmonary artery, either surgically or using catheter-based techniques, assumes utmost importance, while low-risk or nonmassive PE patients can be discharged after initial emergency room assessment and can be managed on outpatient basis. The patients who are hemodynamically stable usually require advanced risk stratification based on clinical risk prediction tools, imaging, specific biomarkers, and presence/absence of comorbidity.^[2] In this review article, we focus upon the various strategies used for risk stratification based on biomarkers and imaging and their current status and clinical validation.

Formulating a Risk Assessment Strategy- Risk Prediction Models

In acute PE patients who are normotensive at presentation, it is imperative to risk stratify for in - hospital or early (30-day) adverse events.

Early risk stratification

The European Society of Cardiology 2019 guidelines and PE Response Team Consortium 2019 guidelines suggest the use of Pulmonary Embolism Severity Index (PESI) or simplified PESI (sPESI) clinical scores as they are most extensively validated. They integrate clinical indicators of acute PE severity with aggravating conditions/comorbidity. PESI I, PESI II, or sPESI 0 reliably predict low-risk PE. Patients in intermediate-risk group can be further classified into low-risk or high-risk category based on the presence/absence of RV dysfunction on imaging using either echocardiography, computed tomography pulmonary angiography (CTPA), or elevated cardiac biomarkers.^[3],[4] It is preferable to monitor these patients closely to allow identification of hemodynamic decompensation at the earliest for expeditious management.^[5] In a recent meta-analysis consisting of 3295 patients from 21 cohort studies, need for newer prognostication models for patients termed as low risk based on low PESI/sPESI scores was highlighted. These authors found signs of RV dysfunction in 34% of patients with early all-cause mortality of 1.8%, confirming that patients with signs of RV dysfunction despite low risk based on clinical validation scores, should be reclassified into intermediate-low-risk category^[6] [Table 1].

Table 1: PESI and sPESI scoring

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New clinical tools for prognostication

Bova and FAST scores are novel risk prediction scores used in small trials of acute PE patients [Table 2].

Table 2: Bova and FAST scoring systems for estimation of risk of pulmonary embolism-related complications within 30 days of acute symptomatic pulmonary embolism diagnosis

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Bova score includes two clinical variables - heart rate and SBP. It gives a score of 1 if a patient's heart rate is ≥110 bpm and a score of 2 if SBP is in the range of 90–100 mmHg. A score of 2 each is assigned for elevated troponins and RV dysfunction detected on imaging study (transthoracic echocardiography/CT pulmonary angiography). In this way, patients can be divided into three categories - 0–2 points low risk, 3–4 points intermediate low risk, and >4 points intermediate high risk.^[7] FAST score has three variables: heart-type fatty acid-binding protein (H - FABP) ≥6 ng/ml or elevated troponins (1.5 points), syncope (1.5 points), and heart rate ≥100 bpm (2 points). The patients are divided into two risk groups as low risk with <3 points and intermediate high risk with ≥3 points. Both of these new scores have integrated imaging or new biomarker assays in risk score model, thereby allowing an integrated assessment.^[8]

Assessment of pretest probability in acute pulmonary embolism

In PE, heightened clinical suspicion is kept for patients having established deep venous thrombosis (DVT). Well's criteria combined with D-dimer assay are useful as a rule-out approach [Table 3]. Usual cutoff levels of D-dimer assay indicating PE are >500 microgram/L. However, recent guidelines recommend using age-adjusted cutoff for D-dimer levels in patients >50 years of age (age ×10 microgram/L), as it helps to reclassify at least 30% of patients as low risk. Thromboembolism risk at 3 months was <1% with this approach in many outcome studies of PE. If Well's score is <2, but D-dimer levels are high, then further testing is definitely recommended^[9],[10] [Figure 1].

Table 3: Well's clinical prediction role for pulmonary embolism

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Figure 1: Flow diagram: Diagnostic and prognostic algorithm in acute pulmonary embolism,
CTPA: Computed tomographic pulmonary angiography, PE: Pulmonary embolism, PESI: Pulmonary Embolism Severity Index, sPESI: simplified Pulmonary Embolism Severity Index, TTE: Transthoracic echocardiography

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Computerized Tomography Pulmonary Angiography: The Gold Standard

CTPA is considered one of the most accurate investigations to assess embolic burden in acute PE. It allows visualization of thromboemboli in main pulmonary artery up till segmental branches. Although it has an 83% sensitivity at a high specificity of 96%, it is associated with a radiation exposure of 3–10 m Sv in a single test (Prospective Investigation of Pulmonary Embolism Diagnosis [PIEOPED] II study). In their meta-analysis, Vedovati et al.^[11] showed that although localization of emboli in central branches of main pulmonary artery was associated with increased 30-day mortality, no association could be correlated with thrombus burden and obstruction index. In an outcome-based study done recently, obstruction index <20% on CTPA could identify low-risk PE patients who did not have associated cardiopulmonary disabilities such as heart failure and lung cancer.^[12]

Based on the results of the available studies, it can be concluded that CTPA has a 96% value to rule out PE, but if clinical suspicion is high, then it reduces to only 60%, so a combined approach for further testing is recommended.

Risk Stratification Using Echocardiography

Echocardiography may be normal in a substantive population of acute PE patients as signs of RV dysfunction typically described in echocardiography studies appear only when there is at least 30% obstruction in pulmonary artery including its branches. Yet, it plays an important role in management of PE patients due to its a availability and ease of use. There is a consensus that 30%–40% of acute PE patients have echocardiographically recognizable RV dysfunction which is useful for monitoring the patients during hospital stay up till discharge.

Echocardiographic Criteria for Right Ventricular Dysfunction

RV dysfunction in a case of PE is defined as RV dilation using any of the following criteria- RV end-diastolic diameter at basal level >30 mm, end-diastolic RV: left ventricular (LV) diameter ratio >1 at basal level, pulmonary hypertension (value derived from either tricuspid regurgitation jet >2.5 m/s or pulmonary acceleration time <90 ms), RV free wall thickness <7 mm, and dilation of the right pulmonary artery (>12 mm/m²). Documenting RV dysfunction using the above criteria indicated two times higher short-term mortality risk (data from 6 studies including 1773 patients).^[13]

Additionally, specific echocardiography findings, namely mobile thrombi in right heart chambers or thrombus in transit, carry high mortality risk and demand urgent embolectomy. This finding has been reported in 4% unselected and in 18% intensive care unit (ICU)-admitted patients of acute PE^[14] [Video 1].

[Additional file 1]

Video 1: A mobile saddle thrombus at bifurcation of main pulmonary artery in a patient of acute submassive pulmonary embolism. On echocardiography, a high left parasternal short-axis view is preferred for proper localization of thrombi in main pulmonary artery, its bifurcation, or at origin of right/left pulmonary arteries.

Echocardiography-Based Risk Stratification Tools

Echocardiography-based risk stratification tools can be divided into the following:

Qualitative parameters

Normally, RV is one-third the size of the LV. When its size appears more than LV visually, it is said to be enlarged. Besides this, regional or global hypokinesia of RV free wall, abnormal septal motion, tricuspid regurgitation, and inferior vena cava (IVC) size and inspiration induced collapsibility, all can be appreciated visually. These findings of right heart strain, although have low negative predictive value, still indicate the possibility of acute PE in an appropriate clinical scenario (53% sensitivity and 83% specificity).^[15]

Another important sign noted on visual assessment is McConnell sign, which refers to severe hypokinesia of whole RV free wall, sparing the apex [Video 2]. It was associated with a 57% higher mortality rate at 3 months in patients who were hemodynamically stable at presentation. So, although it is found in <30% of acute PE patients, its presence on echocardiography adds substantive prognostic value.^[16]

[Additional file 2]

Video 2: Typical McConnell sign (as described in text) in apical four-chamber view.

Quantitative parameters

Quantitative parameters involve documentation of findings of RV pressure overload and dysfunction in a guideline-recommended manner [Figure 2] and [Figure 3].

Figure 2: The typical echocardiography signs seen in a patient of acute pulmonary embolism (PE) are described. (a) Dilated right atrium and right ventricle with moderate tricuspid regurgitation (TR) jet on color flow. (b) Right ventricular systolic pressure (RVSP) of 36 mmHg derived from TR jet velocity signal using continuous-wave Doppler. (c) Pulsed-wave Doppler across pulmonary valve to calculate pulmonary acceleration time (52 ms) and 60/60 sign which is a combination of RVSP <60 mmHg and pulmonary acceleration time <60 ms with mid-systolic notch, a highly specific sign for acute PE. (d) Basal right ventricular:left ventricular ratio is >1 with dilated right ventricle. Basal right ventricular diameter is 38 mm, measured 1 cm below the tricuspid annulus. (e and f) Calculation of right ventricular fractional area change by tracing right ventricular endocardium in diastole and systole, respectively, right ventricular fractional area change in this case was 23% suggesting moderate right ventricular systolic dysfunction

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Figure 3: Various other echocardiographic findings in acute pulmonary embolism which are reproducible and reliable for acute prognostication. (a) Tricuspid annular plane systolic excursion (15 mm) using M-mode at lateral tricuspid annulus. (b) Systolic velocity of tricuspid annulus (7 cm/s) derived by placing tissue Doppler cursor at lateral tricuspid annulus. (c) Calculation of right ventricular myocardial performance index (0.8). (d) Global longitudinal strain of right ventricle (-14%) using speckle tracking. (e) Dilated inferior vena cava (22 mm) seen in subcostal view suggesting raised right atrial pressures. (f) Inferior vena cava collapsibility is <50% calculated by placing M-mode cursor on inferior vena cava and measuring the change in inferior vena cava diameter with respiration

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Right ventricular/left ventricular ratio

Normal RV/LV diameter ratio is <0.6. Ratio >0.9 is considered an independent predictive factor of in-hospital mortality. This measurement is made 1 cm below the tricuspid annulus. Patients who have a persistent ratio >0.9 at hospital discharge were eight times more likely to have recurrent PE and have a hazard ratio (HR) of 4.4 for intensive care unit (ICU) mortality.

60/60 sign

60/60 sign is a combination of RV systolic pressure (RVSP) <60 mmHg and pulmonary acceleration time <60 ms. It was first studied by Kurzyna et al in a cohort of 100 acute PE suspected patients. It is thought to be less operator dependent than the McConnell's sign and is a highly specific sign of acute PE. The largest evaluation of the 60/60 sign was done by Kurnicka et al. in an analysis of 511 consecutive PE patients and found it to be present in 12.9% of the patients.^[17]

Right atrial pressure

This is measured echocardiographically using IVC diameter and collapsibility on inspiration as a surrogate for estimation. Dilated IVC with <50% inspiratory collapse suggests elevated right atrial pressure and is associated with increased ICU mortality with HR 4.3.

Right ventricular systolic pressure

RVSP can be easily calculated from tricuspid regurgitation velocity.

Usually, in acute PE, RVSP ranges from 40 to 55 mmHg, which has HR 1.03 for ICU mortality. If RVSP exceeds 60 mmHg, then signs of chronic pulmonary thromboembolism such as RV hypertrophy, gross pulmonary artery dilatation, and fixed, noncollapsible IVC should be excluded.

Tricuspid annular plane systolic excursion

Tricuspid annular plane systolic excursion (TAPSE) provides a quantitative measure of global RV longitudinal function. Its normal value usually exceeds 60% that of normal mitral annular motion during systole. It is measured by keeping M-mode cursor at the lateral tricuspid annulus. TAPSE <16 mm has been correlated with pre-discharge and 30-day post-discharge complications.

In a prospective, multicenter study of 782 acute PE patients who were normotensive at presentation, RIETE study investigators concluded that TAPSE ≤16 mm correlated with raised pulmonary artery pressures ≈ 53.7 ± 16.7 mmHg, increased end-diastolic diameter of RV ≈ 3.5 ± 0.8 cm, increased RV: LV diameter ratio in end-diastole ~ 1.0 ± 0.3, and hypokinesia of RV free wall ~ in 68%. TAPSE cutoff value of 16 mm at presentation carried HR of 2.3 for any cause and 4.4 of PE-related mortality on follow-up. In conclusion, among patients presenting with acute PE, TAPSE value ≤16 mm identifies high risk while value of >20 mm identifies very low-risk group.^[18]

Two novel parameters incorporating TAPSE have emerged as promising prognostic indicators in recent studies, namely tricuspid regurgitation peak gradient (TRPG)/TAPSE and TAPSE/pulmonary arterial systolic pressure (PASP). These parameters were studied to improve risk stratification in intermediate-risk PE patients on the premise that a ratio of RV function to afterload might be superior in prediction of adverse outcome than longitudinal function alone. TRPG/TAPSE ratio >4.5 and TAPSE/PASP cutoff value 0.4 implied a 21% risk of PE-related short-term mortality, especially in normotensive patients with TAPSE value between 16 and 20 mm.^[19],[20]

Recently, TAPSE was also used to validate a new bedside score named PESI-Echo which helped in a 9.9% improvement in reclassification of at-risk normotensive acute PE patients. PESI-Echo score is calculated using the following formula:

PESI + PASP - TAPSE = PESI-Echo score as TAPSE's value is inversely related to the severity.^[21]

Tissue Doppler-derived systolic velocity S'

This tissue Doppler-based parameter measures RV longitudinal motion similar to TAPSE but is considered more reproducible. Normal velocity at tricuspid lateral annulus is >11 cm/s; in acute PE, it falls below 9 cm/s and is a useful parameter for detecting early change in RV function, but unlike TAPSE, this parameter has been shown to be inferior in prognostication of acute PE patients.

Right ventricular fractional area change

This quantifies the change in RV area during the cardiac cycle.

It is calculated as (RV end-diastolic area − end-systolic area) X 100/end-diastolic area, and values are derived by tracing RV endocardium in diastole and systole using calipers. RV fractional area change correlates with RV ejection fraction (RVEF) calculated by cardiac magnetic resonance (CMR). Its normal value ranges from 35% to 50%.

Right ventricular myocardial performance index

RV myocardial performance index is the ratio of RV isovolumic time divided by ejection time which can be calculated using tissue/pulsed-wave Doppler. It may be used for both the diagnosis of RV dysfunction and the assessment of treatment effectiveness. Normal value is <0.4 by pulsed-wave Doppler and <0.55 by tissue Doppler method.

Right ventricular longitudinal systolic strain

RV longitudinal systolic strain is helpful to quantify subtle changes in RV contractile function. Both RV free wall and global RV strain have been included as prognostic measures in various studies showing robust correlation with biomarker assays, PE outcome, improvement with therapy, and unfavorable outcomes in short-term follow-up. Normal value of RV global longitudinal strain is −24.5% ± 3.8% and that of RV free wall strain is −28.5% ± 4.8%; a cutoff of ≤−15% was an independent predictor of inhospital events in nonmassive acute PE patients. Combination of mean RV free wall strain <−12%, RVEF <40% on three-dimensional echocardiographic imaging, and RVSP >43 mmHg predicts worse prognosis in submassive PE patients^[22] [Table 4] and [Table 5].

Table 4: Diagnostic value of various echocardiography signs of right ventricular dysfunction in acute pulmonary embolism patients (data from pooled analysis)

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Table 5: Prognostic value of specific echocardiography parameters in predicting all-cause and pulmonary embolism-related mortality within 30 days of hospital admission in normotensive acute pulmonary embolism patients

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Combining Compression ultrasonography and Transthoracic Echocardiography in Risk Stratification

Keeping in mind that acute usually originates from deep vein thrombosis (DVT) of lower-limb veins, recent guidelines have emphasized on combining echocardiography with compression ultrasonography of veins for better early risk stratification. This is due to high sensitivity (>90%) and specificity (95%) of compression ultrasonography for DVT diagnosis. In a meta-analysis investigating 8859 patients with acute PE, the presence of concomitant DVT was confirmed as a predictor of 30-day all-cause mortality (odds ratio [OR]: 1.9, 95% confidence interval).^[23]

Laboratory Biomarkers for Acute Pulmonary Embolism Risk Stratification

In acute PE, a cascade of events is initiated due to near-complete/complete thrombotic occlusion of pulmonary vasculature. This sudden blockage in pulmonary artery circulation results in development of acute pressure load on the thin-walled RV, which in response shows stretching of RV wall and dilates as a compensatory mechanism so as to maintain cardiac output. This leads to release of natriuretic peptides and copeptin.

Prolonged state of increased afterload also produces some amount of RV myocardial ischemia leading to myocardial injury as depicted by rise in troponins, H-FABP, and growth-differentiating factor 15 (GDF-15).

Estimating Myocardial Injury Using Biomarkers

In this regard, troponins have a proven role in documenting myocardial injury as well as predicting increased risk of mortality with OR ranging from 5.2 to 5.5 in normotensive patients with acute PE. Age-adjusted cutoffs are useful in further improving its negative predictive value for in-hospital and short-term adverse events which is up to 96% at cutoff >14 pg/mL for patients aged <75 years and >45 pg/mL for those >75 years.

Their main limitation remains detectability only for up to 72 h from index event and delayed release unlike in acute coronary syndromes.^[24]

H-FABP is a protein mainly found in cytoplasm of myocardium, skeletal muscle, and distal renal tubular cells. It is a small molecule with low serum concentrations under normal physiological conditions. Its blood levels start rising within 90 min of myocardial injury, peak in 6 h, and return to baseline after 12–24 h. This rapid release pattern makes it suitable for use in early triage of patients. At a cutoff of ≥6 ng/mL, it poses seven times increased risk of PE-related adverse events with OR of 17 and 33 for all-cause mortality (data from meta-analysis of 1680 patients).^[25] Due to these advantages, such as early rise and low overlap, it is now part of FAST score as described above.

Biomarkers for Increased Myocardial Stretch

Both brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) have established prognostic role in acute PE as both show increased levels in response to RV stretch. They also reflect the severity of RV pressure overload before development of overt hemodynamic compromise.

On admission, BNP values >90 pg/mL and NT-proBNP values value >500 pg/ml have been shown to predict a 10% higher risk of early death and a 23% risk of adverse clinical outcome. These peptides suffer from wide variability of concentrations in various population groups and their delayed release due to slow upregulation of messenger ribonucleic acid. Still, their low levels imply high negative predictive value for adverse in-hospital events.^[26]

Another new molecule which is useful in depicting RV stretch is copeptin. This molecule is similar to vasopressin as it gets released from neurohypophysis following alteration in pulmonary hemodynamics secondary to acute RV pressure overload, but it is more stable than vasopressin which allows its estimation even hours after index event. In various studies, copeptin levels above cutoff value of 24 pmol·L⁻¹ predicted a 6–7 times increased risk for PE-related adverse events and mortality.^[27]

Another new marker which has been studied in the context of PE-related adverse outcome is GDF-15, which is a congener from transforming growth factor and is released in myocardial ischemia and heart failure. Although cutoff values are lacking due to paucity of studies, it has shown almost 95% negative predictive value for 30-day adverse events in a study by Lankeit et al.^[28]

Profiling Right Ventricular Dysfunction Using Combination of Imaging and Serum Biomarkers

As discussed above, all three approaches are useful for risk stratification of normotensive PE patients when used in a judicious stepwise fashion^[29] [Table 6] and [Figure 1].

Table 6: Clinical, laboratory, and echocardiography parameters predicting 30-day pulmonary embolism-related mortality in normotensive acute pulmonary embolism patients- an integrative approach

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The focus of all approaches is documenting RV dysfunction, although cutoff values for each of them may differ. Risk ratio for RV dysfunction assessed by echocardiography/CT was 2.4, for BNP 9.5, NT-pro BNP 5.7, and troponins 8.3 in a retrospective analysis of published data over the last 22 years by Sanchez et al.^[30]

Hence a combined integrative approach toward prognostication is advocated in acute PE as it has additional additive value.

Conclusions

Risk stratification of normotensive acute PE patients is an evolving subject. Cardiac biomarkers and imaging of heart and limb veins have paved the way for rapid and accurate bedside risk stratification. These parameters complement clinical decision-making and therefore have now been included in recently validated risk assessment models for better prognostication of PE patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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