Article, Cardiology

Syncope on presentation is a surrogate for submassive and massive acute pulmonary embolism

a b s t r a c t

Introduction: There are conflicting data regarding the prognostic value of syncope in patients with acute pulmo- nary embolism (APE).

Methods: We retrospectively reviewed data of 552 consecutive adults with computed tomography pulmonary angiogram-confirmed APE to determine the correlates and outcome of the occurrence of syncope at the time of presentation.

Results: Among 552 subjects with APE (mean age 54 years, 47% men), syncope occurred in 12.3% (68/552). Com- pared with subjects without syncope, those with syncope were more likely to have admission systolic blood pres- sure b 90 mm Hg (odds ratio (OR) 5.788, P b 0.001), and an oxygen saturation b 88% on room air (OR 5.560, P b 0.001), Right ventricular dilation (OR 2.480, P = 0.006), right ventricular hypokinesis (OR 2.288, P = 0.018), re- quire mechanical ventilation for respiratory failure (OR 3.152, P = 0.014), and more likely to receive systemic thrombolysis (OR 4.722, P = 0.008). On multivariate analysis, syncope on presentation was an independent pre- dictor of a massive APE (OR 2.454, 95% CI 1.109-5.525, P = 0.03) after adjusting for patients’ age, sex, require- ment of antibiotics throughout hospitalization, peak serum creatinine, admission oxygen saturation b 88% and admission heart rate N 100 bpm. There was no difference in mortality in cases with APE with or without syncope (P = 0.412).

Conclusion: Syncope at the onset of pulmonary embolization is a surrogate for submassive and massive APE but is not associated with higher in-hospital mortality.

(C) 2017

Introduction

Acute pulmonary embolism has an incidence rate of approxi- mately 0.5 to 2 cases per 1000 in the general population per year [1-3]. Registries and hospital discharge datasets of unselected patients with APE or venous thromboembolism yielded 30-day all-cause mortality rates between 9% and 11%, and three-month mortality ranging between 8.6% and 17% [4-6]. Clinical presentation of APE varies widely from he- modynamic instability to clinically silent disease [7], incidentally

? No funding has been received for this manuscript.

?? There are no conflicts of interest to disclose.

* Corresponding author.

E-mail address: [email protected] (H.R. Omar).

discovered on imaging [8] or found on autopsy of patients with sudden unexpected death. The most frequent symptoms in APE are dyspnea (80%), chest pain (52%), and syncope which is present as the first man- ifestation in 9-35% of patients [9-14]. Also, APE was evident in 1.4%- 17.3% of the patients hospitalized for a first episode of syncope [15,16]. In pulmonary embolization, syncope may occur in cases with N 50% occlusion of the pulmonary vasculature [14], or due to tachyarrhyth- mias and bradyarrhythmias related to right ventricular (RV) overload, or due to a vasovagal reflex leading to neurogenic syncope [9]. There are conflicting data concerning the prognostic significance of syncope in patients with APE. Earlier studies suggested that syncope is associat- ed with higher mortality [14,17], however, this was not reproduced in other studies [9,10,12,13,18]. Our Study objectives were to explore char- acteristics, correlates, and outcomes in patients with APE who had syn-

cope as one of the Presenting complaints.

https://doi.org/10.1016/j.ajem.2017.11.014

0735-6757/(C) 2017

298 H.R. Omar et al. / American Journal of Emergency Medicine 36 (2018) 297300

Methods

Study design and study population

This is a retrospective analysis of consecutive adult patients (N 18 years of age) with an International Classification of Disease (ICD- 9-CM) diagnosis of APE who were admitted to Tampa General Hospital in the period between 2010 and 2015. Only subjects with computed to- mography pulmonary angiogram (CTA)-confirmed APE were included in this study, and cases diagnosed with ventilation perfusion lung scan were excluded by a blinded data abstractor. The study author GE collect- ed variables related to baseline demographics, comorbidities, present- ing symptoms, laboratory tests, echocardiography and CTA variables, medications, interventions and outcomes. Data regarding the occur- rence of syncope at the time of hospital admission for APE was collected through chart review of the emergency departments note and the ad- mission history and physical examination note. The objective of this study is to identify characteristics and outcomes of patients hospitalized with APE who experienced syncope as one of the presenting symptoms. The Institutional Review Board approved the study and waived the need for patient consent.

Study definitions

Syncope was defined as a sudden transient loss of consciousness caused by temporary Cerebral hypoperfusion [19]. Syncope definition was not met if subjects had presyncope or lightheadedness. Massive APE was defined as pulmonary embolism associated with systolic blood pressure (SBP) b 90 mm Hg on admission or requiring inotropic support [20]. Submassive APE was diagnosed in patients with SBP N 90 but with either signs of RV dysfunction or Myocardial necrosis [20]. RV dysfunction was diagnosed in our study with the presence of one of the following: right ventricular dilation or hypokinesis on echo- cardiography or elevated B-type Natriuretic Peptide , and myocar- dial necrosis was defined by elevation of troponin I N 0.4 ng/ml [20]. hospital outcomes“>Meeting criteria of massive or submassive APE was adjudicated by the study investigators after chart review taking into account the prespecified above mentioned definitions for each category.

Statistical analysis

Primary analysis compared patients hospitalized with CTA-con- firmed APE with and without syncope on hospital admission. The Sha- piro-Wilk test was used to assess normality of distribution of continuous variables. Because the majority of variables were not nor- mally distributed, comparison of continuous variables between groups was performed using a Mann-Whitney U test and presented as median and interquartile range (IQR). The chi-square test for association was used to compare groups on categorical variables, which were summa- rized using counts and percentages. Univariate odds ratio (OR) and 95% confidence interval (CI) were calculated, along with an accompany- ing p-value using the Mantel-Haenszel common OR estimate. After comparison of patients with or without massive APE to identify univar- iate differences between both groups, a multivariate logistic regression analysis was performed to identify factors present on hospital admis- sion that independently predict the diagnosis of “massive APE”. The out- come variable was massive APE and the predictor variables included those that had a P b 0.05 upon univariate analysis (admission heart rate N 100 bpm, admission oxygen saturation b 88% and peak serum cre- atinine) or those considered to be clinically relevant (requirement of antibiotics throughout hospitalization, patients’ age and sex). The good- ness-of-fit of the model was examined by the Hosmer-Lemeshow test. Statistical analyses were performed using IBM SPSS 21.0 statistical soft- ware (IBM SPSS Version 21.0. Armonk, NY). All statistical significance was assessed using a 2-sided P values. A P-value b 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 552 subjects had CTA-confirmed APE. The age of the study population was 54 +- 17 years, 47% (260/552) were men, 28% (154/552) were African Americans, and 59% (326/552) were European Americans. 21% (118/552) of the cases had prior history of pulmonary embolization and 28% (154/552) had history of cancer. On reviewing the home med- ications, we found that 37% (202/550) of the subjects were on aspirin, 8% (44/550) were on clopidogrel and 42% (233/552) were already on anticoagulant medications. 35% (191/552) of the subjects had concom- itant acute deep venous thrombosis. Comparison of characteristics of patients with CTA-confirmed APE with or without syncope on hospital admission is listed in Table 1.

Clinical and echocardiographic characteristics of patients with pulmo- nary embolism with or without syncope

The prevalence of syncope in the study population on hospital ad- mission was 12.3% (68/552). Subjects who had syncope were more like- ly to have SBP b 90 mm Hg on hospital admission (14.7% vs. 2.9%, univariate OR 5.788, 95% CI 2.459-13.625, P b 0.001). Also, subjects with syncope were more likely to have an oxygen saturation on room air b 88% (15.2% vs. 3.1%, univariate OR 5.560, 95% CI 2.384-12.966, P b

0.001), and lower oxygen saturations on admission (P = 0.021), and were more likely to require mechanical ventilation for respiratory fail- ure (10.3% vs. 3.5%, univariate OR 3.152, 95% CI 1.257-7.908, P =

0.014) compared with patients without syncope. With regards to echo- cardiographic indices, subjects with syncope had higher frequency of RV dilation (42.2% vs. 22.8%, univariate OR 2.480, 95% CI 1.292-4.761, P = 0.006) and hypokinesis (33.3% vs. 17.9%, univariate OR 2.288, 95% CI 1.149-4.556, P = 0.018) compared with those without syncope. Pa- tients with syncope were more likely to receive systemic thrombolysis (7.4% vs. 1.7%, univariate OR 4.722, 95% CI 1.498-14.881, P = 0.008).

In-hospital outcomes

The average duration of hospitalization of the study cohort was

10.5 days and average duration in the intensive care unit 1.9 days. There were no significant differences between patients with APE with or without syncope in hospital duration (P = 0.341) or intensive care unit duration (P = 0.734). A total of 3.1% (17/552) of the patients died in-hospital, including 1.5% (1/68) of cases with preceding syncope and 3.3% (16/484) of cases without syncope (P = 0.412).

Multivariable analysis of factors associated with massive APE

In the multivariate logistic regression model (N = 528, P from Hosmer and Lemeshow = 0.311), we found that the occurrence of syn- cope on presentation was an independent predictor of a massive APE (OR 2.454, 95% CI 1.109-5.525, P = 0.03) after adjusting for patients’ age, sex, requirement of antibiotics throughout hospitalization, peak serum creatinine, admission oxygen saturation b 88% and admission heart rate N 100 bpm. Results of variables included in the multivariate model are listed in Table 2.

Discussion

Our study shows that syncope is a surrogate of submassive APE as evident in the higher frequency of RV dilation and hypokinesis. We have also found that syncope is a surrogate for massive APE where pa- tients with syncope more frequently showed signs of hemodynamic in- stability: they were 5.8 times (P b 0.001) more likely to have a systolic blood pressure b 90 mm Hg, 4.7 times (P = 0.008) more likely to receive

H.R. Omar et al. / American Journal of Emergency Medicine 36 (2018) 297300 299

Table 1

Comparison of characteristics of patients with CTA-confirmed pulmonary embolism with or without syncope on hospital admission.

Table 2

multivariate analysis of factors present on hospital admission that predicts massive APE. Significant P values are listed in bold.

Syncope

No syncope

P-value

OR; 95% CI; P-value

(n = 68)

(n = 484)

Age

1.005 (0.986, 1.025) 0.576

Demographics

Sex

1.360 (0.701, 2.640) 0.363

Age (y, median, IQR)

55 (41, 70)

54 (42, 67)

0.463

HR N 100 bpm on admission

2.443 (1.273, 4.689) 0.007

BMI (Kg/m2, median, IQR)

29.2 (25.8,

29.9 (25.2,

0.917

SO2 b 88% on admission

3.725 (1.365, 10.170) 0.01

36.7)

36.9)

Peak creatinine

1.109 (0.973, 1.264) 0.123

Men % (n)

42.6% (29/68)

47.7%

0.432

Syncope

2.454 (1.090, 5.525) 0.030

(231/484)

Requirement of antibiotics

1.577 (0.815, 3.052) 0.176

HR: heart rate, SO2: oxygen saturation.

Black % (n)

33.8% (23/68)

27.1%

0.245

(131/484)

White % (n)

48.5% (33/68)

60.5%

0.059

(293/484)

Smoking % (n)

22.1% (15/68)

26.9%

0.400

(130/484)

Comorbidities DM % (n)

39.7% (27/68)

30% (145/484)

0.104

COPD % (n)

10.3% (7/68)

15.1% (73/484)

0.294

systemic thrombolysis, in addition to a non-significant trend towards greater requirement of vasopressor support (8.8% vs. 4.3%, P = 0.127). APE prognosis is good in those with normal RV function and no ele- vations in biomarkers [21], with short-term mortality rates approaching

History of cancer % (n)

35.3% (24/68)

26.9%

0.146

1%. In the International Cooperative Pulmonary Embolism Registry

(130/484)

(ICOPER), the 90-day mortality rate for patients with APE and systolic

SLE % (n)

7.4% (5/68)

2.1% (10/484)

0.012

blood pressure b 90 mm Hg at presentation was 52.4% versus 14.7% in

Prior DVT % (n) 20.6% (14/68) 24.8% (120/484)

Prior PE % (n) 19.1% (13/68) 21.7% (105/484)

Prior antiplatelets and anticoagulants

0.449

0.627

the remainder of the cohort [22]. Nonetheless, the presence of syncope was not translated in our analysis into poorer in-hospital outcomes, spe- cifically higher in-hospital mortality -similar to the majority of prior studies. We suspect that our study was not powered enough to deter-

mine any possible difference in in-hospital mortality among subjects

On ASA % (n) 33.8% (23/68) 37% (179/484) 0.612

On Plavix % (n) 13.2% (9/68) 7.2% (35/484) 0.095

with and without syncope. We have only investigated in-hospital but

On Anticoagulants % (n) 39.7% (27/68) 42.6% (206/484)

Clinical features

Chest pain % (n) 58.8% (40/68) 63.8%

0.655

0.422

not intermediate or long-term mortality. Also, up-to-date treatment of APE significantly reduces mortality down to 2.5% [23], and most of the deaths occur if the diagnosis is delayed or never made. Moreover, in ap- proximately 25% of patients, the first manifestation of APE is sudden death, and in N 50% of cases of fatal APE, diagnosis is made during autop- sy [24]. Therefore, sicker patients may die out of hospital or prior to di- agnosis. Those who survive the initial few hours after APE are more likely to survive than die. These factors may have led to the lower in- hospital mortality of appropriately treated cases of APE, further limiting ability to study association of syncope and mortality endpoint. Multi- center studies are therefore needed to best examine the prognostic util- ity of syncope in APE and its association with hard endpoints. Till then, we propose that patients with APE who experienced syncope on pre- sentation be admitted to the hospital for monitoring rather than outpa- tient management, even in those who are deemed hemodynamically stable.

Study limitations include the retrospective design and the moderate number of cases with massive APE, which yielded wide CI on multivar- iate analysis. Due to the lower risk of death in subject with APE receiving appropriate therapy, in-hospital mortality occurred in only 3.1% of the cases, and therefore the study was not powered to detect a possible dif- ference in in-hospital mortality between cases who presented with or without syncope. We also do not have data for intermediate and long- term mortality nor we have data on post-discharge morbidity such as quality of life, Hospital readmissions, or requirements of long-term care or assisted living facility. Larger multicenter studies are required to confirm these findings and examine the short and long-term prog- nostic significance of syncope in patients with APE.

(309/484)

SBP b 90 mm Hg % (n)

14.7% (10/68)

2.9% (14/484)

b0.001

HR N 100 bpm % (n)

27.9% (19/68)

32.2%

0.477

(156/484)

SO2 on RA (%, median, IQR)

0.97 (0.95,

0.98 (0.95,

0.021

0.99)

0.99)

SO2 b 88% on RA % (n)

15.2% (10/66)

3.1% (15/482)

b0.001

RR N 30% (n)

7.4% (5/68)

3.9% (19/484)

0.194

Pressor support % (n)

8.8% (6/68)

4.3% (21/484)

0.127

New onset AFib % (n)

7.4% (5/68)

6.2% (30/484)

0.789

Laboratory

AST (IU/L, median, IQR)

26.2% (17/65)

22.1%

0.778

(100/452)

Peak creatinine (mg/dL, median,

IQR)

0.9 (0.8, 1.2)

0.9 (0.8, 1.2)

0.672

Lactic acid (mmol/L, median, IQR)

1.1 (0.9, 1.8)

1.4 (1.1, 2.9)

0.273

Troponin (ng/mL, median, IQR)

0.05 (0.02, 0.3)

0.05 (0.01,

0.711

0.58)

BNP (pg/dL, median, IQR)

77 (43, 291)

31 (12, 225)

0.111

Acute DVT % (n)

48.2% (27/56)

42.4%

0.416

(154/363)

Echocardiography

RV dilation (echo) % (n)

42.2% (19/45)

22.8% (66/290)

0.005

RV hypokinesis (echo) % (n)

33.3% (15/45)

17.9% (52/290)

0.016

Treatment

Mechanical ventilation % (n)

10.3% (7/68)

3.5% (17/484)

0.02

BiPAP support % (n)

2.9% (2/68)

1.7% (8/484)

0.456

Systemic thrombolysis % (n)

7.4% (5/68)

1.7% (8/484)

0.014

Outcomes

Hospital duration (d, median, IQR)

6 (3, 15)

6 (3, 11)

0.341

ICU duration (d, median, IQR)

1.9 +- 5.8

1.9 +- 6.8

0.734

Survived hospitalization % (n)

98.5% (67/68)

96.7%

0.412

(468/484)

BMI: body mass index, DM: Diabetes Mellitus, COPD: chronic obstructive pulmonary dis- ease, SLE: systemic lupus erythematosus, DVT: deep venous thrombosis, PE: pulmonary embolism, SBP: systolic blood pressure, HR: heart rate, SO2: oxygen saturation, RA: room air, RR: respiratory rate, BNP: B-type natriuretic peptide, RV: right ventricle, BiPAP: bilevel positive pressure ventilation.

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