Central versus Peripheral Pulmonary Embolism: Analysis of the Impact on the Physiological Parameters and Long- Term Survival

Research Article

Austin J Pulm Respir Med 2015; 2(2): 1026.

Central versus Peripheral Pulmonary Embolism: Analysis of the Impact on the Physiological Parameters and Long- Term Survival

Alonso-Martínez JL*, Anniccherico-Sánchez FJ, Urbieta-Echezarreta M, Villar-García I and RojoÁlvaro J

Department of Internal Medicine, Hospital Complex of Navarra, Spain

*Corresponding author: Alonso-Martínez JL, Department of Internal Medicine, Hospital Complex of Navarra, Irunlarrea 6, 31008 Pamplona, Navarra, Spain

Received: August 05, 2015; Accepted: September 01, 2015; Published: September 03, 2015

Abstract

Background: Studies aimed at assessing whether the emboli lodged in the central pulmonary arteries carry a worse prognosis than more peripheral emboli have yielded controversial results.

Patients and Methods: Consecutive patients diagnosed with acute symptomatic Pulmonary Embolism (PE) by means of computed tomography angiography were evaluated at episode index and traced through the computed system of clinical recording and following-up. Central PE was diagnosed when thrombi were seen in the trunk or in the main pulmonary arteries and peripheral PE when segmental or sub segmental arteries were affected.

Results: A total of 530 consecutive patients diagnosed with pulmonary embolism were evaluated, 255 patients had central PE and 275 patients had segmental or sub segmental PE. Patients with central PE were older, had higher plasma levels of NT-ProBNP, Troponin I, D-dimer, alveolar-arterial gradient and shock index (p<.001 respectively for each one).

Patients with central PE had an all-cause mortality of 40%, while patients with segmental or sub segmental PE had an overall mortality of 27%, OR 1.81 (CI 95% 1.16-1.9).

Survival was lower in patients with central PE than in patients with segmental or sub segmental PE, even after to avoid confounders (p=.018).

Conclusion: Besides greater impact on hemodynamics, gas exchange and right ventricular dysfunction, central pulmonary embolism associates a shorter survival and an increased long-term mortality.

Keywords: Venous thromboembolic disease, Pulmonary embolism, Central pulmonary embolism, Survival, Cardiac peptides

Introduction

With the increasing use of the Computed Tomography (CT) angiography as the main diagnostic method in pulmonary thromboembolism, new approaches for categorizing the severity of pulmonary embolism have been conducted mainly based on thrombus burden and its impact on the right ventricle [1-17].

Data from radiographic studies which used CT angiography to evaluate the prognostic factors associated with pulmonary embolism (such as the relationship between the diameter of the right ventricle and the diameter of the left ventricle, the bowing of the interventricular septum [1-4], the thrombus burden [14-17], the reflux contrast to the cava [18], and the diameter of the pulmonary artery regarding the azygos vein), have been studied as prognostic factors of morbidity and mortality in the context of acute pulmonary thromboembolism.

The impact of pulmonary embolism on the right ventricle measured by biomarkers and D-dimer also has been correlated with the thrombotic burden in several investigations [19,20], and recently the European Society of Cardiology has included the right ventricular dysfunction in the risk assessment of the pulmonary embolism [21] evaluated by echocardiography as well as measured by CT, though in both cases the prediction of an adverse outcome has been difficult to standardize.

The location of the thrombi in the pulmonary arterial tree has received some attention as prognostic factor. Prognosis is worse when the trunk or main pulmonary arteries are occupied by thrombi with either complete or incomplete occlusion [22-25], although this has not been shown consistently in all studies, since several of them have been unable to demonstrate an association between image scores and mortality [26-28].

Although many radiologists consider a pulmonary embolism is massive when thrombi are visualized in the main pulmonary arteries, the current criterion is the state of the blood pressure, categorizing the patients as normotensive or hypotensive patients, with the latter needing fibrinolysis. However, a number of normotensive patients will develop clinical deterioration, requiring subsequent thrombolysis. Therefore, this has contributed to conclude that size does not matter [29].

A recent meta-analysis assessing the localization of emboli visualized at CT angiography was useful for the stratification of patients [30], though there was no correlation between the obstruction index and prognosis. Another meta-analysis has concluded that the strongest radiological predictive value for adverse outcome in patients with pulmonary embolism is the right to left ventricular ratio measured on CT [31].

However, the analysis of the adverse outcomes using as predictive tools the CT angiography and echocardiography, evaluating the burden and the localization of clots or the overload or dysfunction of the right ventricle, both have been estimated at short-term (i.e. inhospital and 30-days mortality or ICU admission).

To our knowledge there are not studies approaching the long-term prognosis of pulmonary embolism affecting the main pulmonary arteries. Therefore, our aim was to study the prognostic significance of pulmonary embolism affecting pulmonary arteries of different size and to check the survival at long-term differentiating central pulmonary embolism and peripheral pulmonary embolism.

Patients and Methods

In the period 2004-2013, all consecutive outpatients hospitalized on the Internal Medicine Service with a diagnosis of acute symptomatic hemodynamically stable pulmonary embolism, diagnosed by helical chest CT, were evaluated within 24 hours of admission. This study was approved by the local ethics committee. Because the study was observational and did not interfere with diagnostic or therapeutic work-up, informed consents were not obtained. Each patient approved and signed the informed consent for radiologic contrast administration.

Study design and methods

Systematically, we recorded on admission blood pressure, shock index (the ratio of heart rate to systolic blood pressure), heart and respiratory rates, blood gases value before supplementary oxygen administration, electrocardiographic recording, days of symptoms up to diagnosis, and calculated alveolar-arterial difference of oxygen. Alveolar-arterial oxygen gradient was calculated as:

FiO2(Pb-47) _ PACO2/R _ F1O2/R (1-R) (PaCO2/R) _ PaO2

where FIO2 is the O2 inspiratory fraction, Pb is the barometric pressure and PACO2 is alveolar CO2 pressure, PaCO2 is arterial CO2 pressure, assumed to be equal to PCO2, and PaO2 is arterial oxygen pressure. R is the respiratory exchange ratio, set to be 0.8.

Single-slice helical CT was used for diagnosis in 23% patients and multi-detector scanner of 64 rows was used for diagnosis in the rest, both were General Electric devices (Medical Systems, Milwaukee, WI). One mm slices and standard sequential acquisition were obtained in every patient. Breath-hold acquisition was employed. After the intravenous injection of contrast material, the scanning area comprised the chest and upper abdomen, acquiring images in the cranio-caudal direction. Central PE was diagnosed when thrombi were visualized in the main trunk of the pulmonary artery and/or in right or left main pulmonary arteries. Peripheral PE was diagnosed when thrombi were seen exclusively in segmental or sub segmental pulmonary arteries. Each scan was read by a radiologist as in usual clinical practice. Radiologists were blinded to the clinical, laboratory outcomes and survival. Subsequently, the scans were also reviewed by investigators belonging to Internal Medicine Service.

Thrombotic burden was calculated with the formula for the CT obstruction index [32] applied to the initial CT angiography, which was diagnostic of pulmonary embolism. Each lung is considered to have 10 arteries, 3 in the upper lobe, 2 in the middle lobe and lingula and 5 in the lower lobe. The presence of embolus in a segmental artery was scored as 1 point, and emboli in the most proximal arterial level was scored as the value equal to the number of segmental arteries arising distally. A weight factor was assigned depending on the degree of vascular obstruction: 1 point when the thrombus was partially occlusive, and 2 points with total occlusion. Therefore, maximal CT obstruction index is 40 points. The percentage of vascular pulmonary obstruction was calculated as follows: n.d/40×100, where n is the value of the proximal thrombus in the pulmonary arterial tree equal to the number of segmental branches arising distally and d is the degree of obstruction.

The degree of pulmonary obstruction was calculated by the clinicians who were taking care the patients, who were the authors belonging to Internal Medicine. We scored 2 points for the artery where the irrigated territory of a pulmonary infarction was seen and when contrast was not observed distal to the thrombus. The rest of the cases were scored 1 point.

In every patient, blood was drawn within 24 hours of admission for pro-BNP and Troponin I determination. Plasma D-dimer levels were measured previously in the emergency ward.

Standard therapy consisted of enoxaparin 1 mg/kg twice a day for 3 to 5 days, initiation of oral anticoagulants (coumarone) on the first day of hospitalization, overlap of enoxaparin and oral anticoagulants for a minimum of 3 days, and cessation of enoxaparin when INR was greater than 2. During hospitalization fibrinolysis was subsequently indicated in 3 patients due to hemodynamic instability. After treatment with enoxaparin, secondary prophylaxis was made with direct action anticoagulants in 7 patients: Apixaban 2 patients, Rivaroxaban 4 patients and Dabigatran 1 patient.

Death rate was defined as deaths by all causes during hospitalization and those occurred at follow-up. The cause of death by recurrent pulmonary embolism was considered when new thrombotic material in the pulmonary arterial tree was demonstrated either with angio-CT or lung scan and also when the patient had a sudden death with dyspnea.

Cardiovascular death included patients who died because of myocardial infarction, heart failure or reported ventricular dysrrhytmias. Death by all causes was considered in the mortality rate.

Statistical analysis

All continuous variables were tested for normal distribution with the Kolmogorov-Smirnov test. Continuous variables are expressed as median and Interquartile Range (IQR) for variables without normal distribution and as mean ± Standard Deviation (SD) for variable with Gaussian distribution.

Comparison of 2 means was performed with the t test for normally distributed variables and with the Mann-Whitney U test for non-Gaussian variables. Fisher exact test and x2 test were used for proportional comparisons.

Survival analysis was made by using the Mantel-Haenszel test. We tested survival at several times after the index episode in order to see the short, the mid and the long-term survival.

The independence of significant variables obtained from bivariant statistic analysis for central pulmonary embolism was tested with logistic regression by means of a step by step process, eliminating those variables without a level of significance <.05 up to reach of the last useful model. We used standardized coefficient due to the wide variability in measurement units.

All statistical tests were 2-tailed, and a p < 0.05 was considered statistically significant. Values of p greater than 0.05 were considered non-significant.

Results

In the period from January 2004 to December 2013, five hundred and thirty patients consecutively hospitalized because of acute pulmonary embolism were analyzed. Patients were traced during a total time of twelve years.

The median time of follow-up was of 34 (IQR 52) months. The median age was of 76 (IQR 16) years, male 45%. Demographic and baseline data are depicted in Table 1.

Central pulmonary embolism was diagnosed in 255 (48.5%) patients and segmental or sub-segmental (peripheral) thromboembolism in 275 (51.5%) patients. Median age of central pulmonary embolism was 78 (IQR 13) years, while median age of peripheral pulmonary embolism was of 74 (IQR 18) years (p<.001). The concordance between the readings of CT angiography by radiologist and internist doctors was of Kappa 0.87.

Fifty nine (23%) patients with central pulmonary embolism and 56 (20%) patients with peripheral pulmonary embolism had previous cardiac disease (p=.43). Twenty five (10%) patients with central pulmonary embolism and 39 (14%) patients had chronic respiratory disease (p=.11).

Patients with central pulmonary embolism showed a smaller proportion of clinical deep venous thrombosis (28% versus 37% p<.05 CI 95% 0.019-0.17), higher burden of pulmonary thrombi and a higher plasma levels of NT-ProBNP, Troponin I, D-dimer, alveolar to arterial gradient of oxygen, shock index and respiratory rate (p<.001 in each one of the above), while they showed lower arterial partial pressure of oxygen (p<.001), lower arterial partial pressure of carbon dioxide (p<.001) and systolic blood pressure (p<.05) than patients with peripheral pulmonary embolism (Table 1).