Background
There is limited information on the utility of certain echocardiographic measurements, such as right ventricular (RV) strain analysis, in predicting mortality in patients with acute pulmonary embolism (PE).
Methods
A total of 211 patients with acute PE admitted to a medical intensive care unit (ICU) were retrospectively identified. Echocardiographic variables were prospectively measured in this cohort. The focus was on ICU, hospital, and long-term mortality.
Results
The mean age was 61 ± 15 years. Median Acute Physiology and Chronic Health Evaluation IV and simplified Pulmonary Embolism Severity Index scores were 60 (interquartile range, 40–71) and 2 (interquartile range, 1–2), respectively. Thirty-eight patients (18%) died during the sentinel hospitalization (13% died in the ICU). A total of 61 patients (28.9%) died during a median follow-up period of 15 months (interquartile range, 5–26 months). The echocardiographic variables associated with long-term mortality (from PE diagnosis) were ratio of RV to left ventricular end-diastolic diameter (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2–4.8), tricuspid annular plane systolic excursion (HR, 0.53; 95% CI, 0.31–0.92), and RV–right atrial gradient (HR, 1.02; 95% CI, 1.01–1.4). ICU mortality was associated with ratio of RV to LV end-diastolic diameter (HR, 4.4; 95% CI, 1.3–15), RV systolic pressure (HR, 1.03; 95% CI, 1.01–1.05), tricuspid annular plane systolic excursion (HR, 0.4; 95% CI, 0.18–0.9), and inferior vena cava collapsibility < 50% (HR, 4.3; 95% CI, 1.7–11). These variables remain significantly associated with mortality after adjusting by Acute Physiology and Chronic Health Evaluation IV score, Pulmonary Embolism Severity Index score, or the use of thrombolytic agents. RV strain parameters were not correlated with hospital or long-term mortality.
Conclusions
Four simple parameters that measure different aspects of the right ventricle (ratio of RV to left ventricular end-diastolic diameter, RV systolic pressure, tricuspid annular plane systolic excursion, and inferior vena cava collapsibility) were independently associated with mortality in patients presenting with acute PE who were admitted to the ICU.
Acute pulmonary embolism (PE) has an annual incidence of 69 per 100,000 and causes significant morbidity and mortality. Epidemiologic data from European countries have estimated the number of deaths from venous thromboembolism at 12%. The prognosis of patients with PE is negatively influenced by the presence of hemodynamic instability or shock, which is defined as systolic blood pressure ≤ 90 mm Hg or mean arterial pressure ≤ 65 mm Hg.
Echocardiography is a relatively simple and widely available imaging technique that is routinely used for the initial assessment of patients with acute PE. This noninvasive tool allows the evaluation of right ventricular (RV) size and function, which is essential because RV dysfunction in patients with PE is common (from 40% to 70%) and, more important, relates to poor clinical outcomes. In hemodynamically stable patients with PE, high clot burden is associated with RV failure, clinical deterioration, and death. Several echocardiographic findings are associated with the RV dysfunction and severity of PE, such as the McConnell’s sign, increased RV end-diastolic diameter (EDD), and RV free wall hypokinesis. In recent years, quantitative echocardiographic assessment of RV function has gained increasing interest in diseases that affect RV function, such as pulmonary hypertension. However, there are limited data on the use of RV echocardiographic determinations in risk stratification of patients with acute PE.
In addition to quantitative assessment of RV function, the analysis of RV strain and strain rate by two-dimensional speckle-tracking strain has been proposed to allow the quantification of RV myocardial deformation. The speckle-tracking technique is angle independent, which enables an assessment of both regional and global myocardial strain from two-dimensional strain imaging. The analysis of RV strain and strain rate may provide prognostic information and could help in the stratification of patients with acute PE. In the present study, we examined whether a comprehensive assessment of RV function by integrating qualitative and quantitative echocardiographic methods could predict outcomes in patients with acute PE admitted to a medical intensive care unit (ICU). Because the relative value of each determination remains unclear, we sought to identify the most important echocardiographic parameters that predict medical ICU, hospital, and long-term mortality in patients with acute PE.
Methods
Subjects and Study Protocol
This was a single-center, retrospective cohort study that was approved by the Cleveland Clinic Institutional Review Board. We identified patients with acute PE admitted to Cleveland Clinic between February 2009 and January 2013 using the International Classification of Diseases, Ninth Revision, codes for PE and pulmonary infarction (415.1 and V12.51). For this analysis, we identified 235 patients who (1) had confirmed diagnoses of PE by computed tomographic angiography of the chest and/or a ventilation-perfusion scan and (2) underwent transthoracic echocardiography <72 hours after the diagnosis of PE. All transthoracic echocardiograms were reviewed by two physicians (D.K. and T.Y.), who were blinded to the patients’ clinical data. All echocardiography was performed before any intervention (thrombolytic therapy or thrombectomy). Patients who underwent any of the above interventions were excluded from the study. In addition, we excluded 24 patients with suboptimal transthoracic echocardiographic images that precluded speckle-tracking analysis. Therefore, a total of 211 patients with acute PE were included in the final analysis.
The following data were collected in all patients: demographic characteristics (age, gender, and ethnicity), clinical presentation (oxygen saturation and vital signs at admission), medical history (cancer, metastasis status, and chronic lung disease), and laboratory determinations (serum troponin levels, brain natriuretic peptide, and N-terminal pro–brain natriuretic peptide). The diagnosis of PE was confirmed by contrast-enhanced chest computed tomography ( n = 203) or a high-probability ventilation-perfusion scan ( n = 8). Central PE was defined as saddle embolus or thrombus in the main pulmonary arteries. Lobar PE was defined as any thrombus in the lobar branches of pulmonary arteries. Segmental and subsegmental PE was defined as thrombus in the distal branches of pulmonary arteries. Hemodynamic instability was considered present if vasopressors were used on admission, systolic blood pressure was ≤90 mm Hg, or mean arterial pressure was ≤65 mm Hg. All patients received anticoagulation during the course of admission. Thrombolytic therapy was used if considered appropriate by the admitting physician.
The primary outcomes of interest were ICU (death that occurred during the ICU stay), hospital (death that occurred at any point during the hospitalization, including the ICU stay), or long-term (death at any time from the initial diagnosis of PE to the end of follow-up, i.e., July 2013) all-cause mortality. Clinical deterioration was defined as the need for mechanical ventilation and/or hemodynamic instability. Other clinical outcomes (need for mechanical ventilation and length of stay) were also considered. The analysis for length of ICU or hospital stay was performed only in those patients who survived the hospitalization. Survival status was assessed by reviewing our electronic medical records and the Social Security Death Index.
Echocardiography and Strain Analysis
We evaluated all the echocardiograms and performed measures offline, using syngo Dynamics (Siemens Medical Solutions USA, Inc, Malvern, PA). Transthoracic echocardiography was performed by experienced sonographers using commercially available ultrasound systems. A large number of echocardiographic variables of RV and left ventricular (LV) size and function were measured using current guidelines.
Measured RV parameters included RV outflow tract diameter and time-velocity integral, RV EDD (basal, midcavity, and longitudinal), RV end-diastolic wall thickness, RV systolic pressure (RVSP), RV-to-LV EDD ratio (RV/LV EDD), right atrial (RA) midcavity diameter, and end-systolic area. Tricuspid annular plane systolic excursion (TAPSE) was measured using two-dimensional images as previously described ( Figure 1 ). RV area was measured at end-diastole by tracing the endocardial border in the apical four-chamber view and including tricuspid leaflets, and trabeculations as part of the chamber. RVSP was derived from peak tricuspid regurgitation (TR) jet velocity, using the simplified Bernoulli equation and combining this value with an estimated RA pressure. We determined whether echocardiograms showed paradoxical septal motion, hypokinesia of the RV free wall, and McConnell’s sign (hypokinesia of the mid-RV free wall with preserved motion of the RV apex). LV ejection fraction (LVEF) was measured using the biplane Simpson’s method. Other parameters for LV quantification were measured according to American Society of Echocardiography recommendations. All RV and LV parameters were measured twice, and the mean was then used for analysis. We also measured the inferior vena cava (IVC) diameter and its collapsibility.
RV longitudinal strain and strain rate were measured offline (syngo, Velocity Vector Imaging; Siemens Medical Solutions USA, Inc). All strain determinations were performed by one author (K.K.), who was blinded to clinical data. The endocardial border of the right ventricle was traced from an apical four-chamber view, and segmental strain and strain rate curves were generated automatically. Six segments were analyzed for each patient: basal RV free wall, mid-RV free wall, apical RV free wall, apical septum, midseptum, and basal septum. Global RV free wall and septal scores were calculated from the mean of the three free wall regions and the three septal regions, respectively ( Figure 2 ).
Statistics
Means and SDs, medians and interquartile ranges (IQRs), and numbers of patients and percentages are provided as appropriate. Binary logistic regression was used to identify echocardiographic variables predictive of ICU or hospital mortality. Results are expressed as odds ratios (OR) with corresponding 95% confidence intervals (95% CIs). OR are reported on the basis of a relevant unit of change, as shown in the tables. When mentioned, these models were also adjusted by the Acute Physiology and Chronic Health Evaluation (APACHE) IV score and by the simplified Pulmonary Embolism Severity Index (PESI). APACHE IV provides risk stratification in the intensive care setting. APACHE requires the input of many clinical variables into a logistic regression equation, which predicts hospital mortality and ICU length of stay. Meanwhile, the simplified PESI is a scoring system that assigns points for selected clinical variables. A total point score of zero indicates a low risk for mortality, while a score ≥1 indicates a higher risk for death. The simplified PESI estimates the risk for 30-day mortality in patients with acute PE.
Survival at each time point was assessed by Kaplan-Meier methodology. The start point was the date of PE diagnosis. The end of follow-up was marked by the patient’s death. Patients were censored at the end of study follow-up in July 2013. All-cause mortality adjusted for age and gender was evaluated by Cox regression statistics. Results are expressed as hazard ratios (HRs) with corresponding 95% CIs. The HR is significant when the 95% CI does not include the value 1 (unity). Variables with HRs < 1 are associated with a lower risk for the outcome tested. For instance, an HR of 0.55 signifies a decrease of 45% per unit of change of the variable (e.g., 1-cm increase). For a 2-cm increase, the HR is 0.55 2 = 0.30, representing now a 70% decrease in the risk for the outcome tested. A random forest model was used to rank the importance of variables for the classification analysis. All P values reported are two tailed. P values < .05 were considered significant. The statistical analyses were performed using SPSS version 17 (SPSS, Inc, Chicago, IL) and Salford Systems (San Diego, CA).
Results
Overall Patient Characteristics
We included a total of 211 patients in the final analysis. Patients had a mean age of 61 ± 15 years, and 107 (51%) were women. The majority were Caucasian (77%) or African American (22%). Three-quarters of the patients ( n = 160 [76%]) were initially admitted to the ICU. Risk factors for the development of PE are shown in Table 1 . Interestingly, 32 patients (15%) had at least two risk factors for PE. Among patients with histories of malignancy ( n = 70), 34 were receiving chemotherapy at the diagnosis of PE, and 29 patients had confirmed metastatic disease.
| Etiology | Total ( n = 211) |
|---|---|
| Idiopathic | 91 |
| Cancer | 70 |
| Immobilization | 23 |
| Recent surgery | 22 |
| Use of contraception methods | 2 |
| Thrombophilia | 3 |
In 87% of patients, the qualifying event was the first episode of PE. Meanwhile, 13% of patients had prior episodes. PE was located in the central, lobar, and segmental or subsegmental branches of the pulmonary artery in 23%, 41%, and 36% of patients, respectively. The average APACHE IV score and simplified PESI score were 60.3 ± 27 and 1.8 ± 1.0, respectively. Mechanical ventilation was required in 26% patients. A total of 25 patients (12%) were considered hemodynamically unstable at admission, while 48 patients (23%) became unstable during the course of the hospitalization. Intravenous thrombolytic therapy was administered to 19 patients (9%), while surgical embolectomy was performed in only one patient (0.5%).
Outcomes
Twenty-eight patients (13%) died during the ICU admission, and a total of 38 patients (18%) died during the hospitalization. Median length of ICU stay was 2.8 days (IQR, 2–5 days); median length of hospital stay was 11.1 days (IQR, 8–18) days. Patients who died during hospitalization had lower TAPSE and LV EDDs and higher TR jet velocities, RVSPs, RV/LV EDD ratios, and a higher percentage of patients had leftward shifting of the interventricular septum (IVS) or absence of IVC collapsibility ( Table 2 ). A total of 62 patients (29.4%) died during a median follow-up of 15 months (IQR, 5–26) (i.e., long-term mortality).
| Determinations | Overall population | Hospital survival | Hospital death | P (Student t or Fisher exact test) | |
|---|---|---|---|---|---|
| n | Mean ± SD or % | Mean ± SD or n (%) | Mean ± SD or n (%) | ||
| n | 211 | 173 (82) | 38 (18) | ||
| RA end-systolic diameter (cm) | 211 | 4.5 ± 1.1 | 4.5 ± 1.1 | 4.7 ± 1.2 | .44 |
| RA end-systolic area (cm 2 ) | 211 | 14.7 ± 6.4 | 14.7 ± 6.4 | 14.9 ± 6.3 | .83 |
| RV basal diameter (cm) | 211 | 4.2 ± 0.9 | 4.2 ± 0.9 | 4.1 ± 0.9 | .54 |
| RV midventricular diameter (cm) | 211 | 3.8 ± 0.9 | 3.7 ± 0.9 | 4.0 ± 1.0 | .21 |
| RV longitudinal dimension (cm) | 211 | 8.0 ± 1.0 | 8.0 ± 1.2 | 7.9 ± 0.9 | .78 |
| RV wall thickness, subcostal view (cm) | 211 | 0.17 ± 0.20 | 0.18 ± 0.23 | 0.13 ± 0.17 | .20 |
| TAPSE (cm) | 211 | 1.7 ± 0.5 | 1.7 ± 0.5 | 1.5 ± 0.4 | .02 |
| RV ejection fraction (%) | 211 | 46.3 ± 14 | 47 ± 14 | 45 ± 14 | .50 |
| Maximum TR jet velocity (m/sec) | 166 | 3.5 ± 1.4 | 3.3 ± 1.3 | 4.1 ± 1.5 | .01 |
| Estimated RVSP (mm Hg) | 164 | 44 ± 19 | 42 ± 17 | 52 ± 23 | .01 |
| RVOT TVI (cm) | 103 | 13.9 ± 4.4 | 14.0 ± 4.6 | 13.1 ± 3.9 | .43 |
| TRV/RVOT TVI | 102 | 0.23 ± 0.11 | 0.23 ± 0.11 | 0.26 ± 0.09 | .32 |
| RVOT diameter (cm) | 211 | 3.6 ± 0.6 | 3.6 ± 0.6 | 3.6 ± 0.6 | .81 |
| Peak systolic lateral RV annular velocity (cm/sec) | 165 | 13.2 ± 5.0 | 13.4 ± 4.7 | 12.1 ± 5.4 | .19 |
| RV/LV EDD ratio | 211 | 0.91 ± 0.27 | 0.88 ± 0.26 | 1.01 ± 0.31 | .01 |
| LV EDD (cm) | 211 | 4.3 ± 0.7 | 4.3 ± 0.7 | 4.1 ± 0.8 | .02 |
| LVEF (%) | 211 | 55.8 ± 10 | 56.2 ± 9.3 | 53.8 ± 11.5 | .18 |
| McConnell’s sign | 211 | ||||
| Absent | 181 | 86 | 151 (87) | 30 (79) | .20 |
| Present | 30 | 14 | 22 (13) | 8 (21) | |
| RV free wall hypokinesia | 211 | ||||
| Absent | 150 | 71 | 127 (73) | 23 (61) | .12 |
| Present | 61 | 29 | 46 (27) | 15 (39) | |
| Leftward shifting of the interventricular septum | 211 | ||||
| Absent | 172 | 82 | 146 (84) | 26 (68) | .04 |
| Present | 39 | 18 | 27 (16) | 12 (32) | |
| IVC size (cm) | 139 | 2.1 ± 0.5 | 2.1 ± 0.5 | 2.1 ± 0.5 | .98 |
| Patients not on MV | 99 | 2.0 ± 0.5 | 2.1 ± 0.5 | 2.0 ± 0.4 | .75 |
| Patients on MV | 40 | 2.2 ± 0.5 | 2.3 ± 0.4 | 2.1 ± 0.6 | .28 |
| IVC collapsibility ≥ 50% ∗ | 99 | ||||
| Absent | 33 | 33 | 28 (30) | 5 (71) | .04 |
| Present | 66 | 67 | 64 (70) | 2 (29) | |
Echocardiographic Determinations and Mortality Outcomes
Echocardiography was performed a median of 16.8 hours (interquartile range, 0–24) hours after the diagnosis of PE. Relevant echocardiographic measurements are shown in Table 2 . RV strain was obtained in 203 patients. Of these, 110 (54%) had optimal, 89 (44%) suboptimal, and four (2%) poor echocardiographic windows for strain acquisition.
Several echocardiographic parameters were associated with ICU mortality in an unadjusted binary logistic regression model ( Table 3 ). However, after adjusting ICU mortality for APACHE IV score, only decreased LVEF, increased LV EDD, increased estimated RVSP, and absence of IVC collapsibility were associated with high ICU mortality ( Table 3 ). Of the echocardiographic variables that were associated with ICU mortality, random forest analysis identified RV/LV EDD ratio as the variable with the highest importance.
| Echocardiographic parameter | Unadjusted | Adjusted | ||
|---|---|---|---|---|
| OR | 95% CI | OR | 95% CI | |
| RA systolic dimension (per 1-cm change) | 1.50 | 1.05–2.20 | ||
| LV EDD (per 1-cm change) | 0.41 | 0.22–0.77 | 0.44 | 0.23–0.84 |
| LVEF (per 10% change) | 0.64 | 0.43–0.98 | ||
| RV/LV EDD ratio (per 0.1 change) | 1.16 | 1.02–1.32 | ||
| Estimated RVSP (per 10 mm Hg change) | 1.40 | 1.1–1.80 | 1.35 | 1.05–1.74 |
| Maximum TR jet velocity (per 1 m/sec change) | 1.46 | 1.08–1.99 | ||
| IVC collapsibility ≥ 50% (presence) | 0.25 | 0.1–0.67 | 0.20 | 0.07–0.58 |
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