a b s t r a c t

Purposes: The objective of this study was to identify clinical factors associated with delayed diagnosis of acute pulmonary embolism (PE) in the emergency department (ED).

Basic procedures: A retrospective observational study was performed at three University affiliated Hospitals; 436 consecutive patients who presented to the ED with an acute PE confirmed by chest computed tomography from 2008 to 2011 were included. Patients were divided into 3 groups: group 1, PE was diagnosed while the patient was still in the ED; group 2, PE was diagnosed during hospitalization; group 3, patients who were sent home with a wrong alternative diagnosis and returned to the ED and were diagnosed of PE. Main findings: One hundred forty-six patients (33.5%) had a delayed diagnosis of PE–21.5% belong to group 2 and 11.9% to Group 3. Chronic coexisting medical conditions like asthma or chronic obstructive pulmonary disease were independent predictors of a delayed diagnosis in patients who were admitted to hospital whereas non-specific and less severe symptoms like the presence of pleuro-mechanic Thoracic pain, fever, hemoptysis, or the presence of a pulmonary infiltrate in chest x-ray were independent predictors of a delayed diagnosis in patients who were sent home.

Principal conclusions: Delay in diagnosis of acute PE is frequent despite current Diagnostic strategies. Patients are sent home or admitted to hospital with a wrong diagnosis depending on clinical presentation or coexisting medical conditions.

(C) 2013

Introduction

Prompt recognition of pulmonary embolism (PE) remains a challenge. Patients with acute PE often have nonspecific symptoms, and as a result, the diagnosis is sometimes delayed [1,2]. Early diagnosis may reduce morbidity and mortality. In fact, previous studies have reported that patients diagnosed within 48 hours of arrival at the emergency department (ED) had better outcomes [3]. Accordingly, patient safety could benefit if clinicians had data to define the typical clinical profile of patients presenting to the ED for whom the accurate diagnosis of PE was not made on initial presentation. Factors associated with the timing of diagnosis have been reported earlier but only in patients who were admitted to hospital [4-8]. Patients who were sent home with a wrong diagnosis have not been included in these previous studies.

We conducted a retrospective review of patients with acute PE evaluated in different EDs to identify the prevalence and clinical

* Corresponding author. Emergency Department, Hospital Universitario Infanta Cristina, 28981 Parla, Madrid. Tel.: +34 911913038.

E-mail address: [email protected] (J. Torres-Macho).

factors associated with a delayed diagnosis. We also analyzed whether patients with a delayed diagnosis showed more severe PE or worse outcomes as compared to patients who had PE diagnosed without a significant delay.

Methods

Study design

We performed a retrospective observational study at three University affiliated Hospitals in Madrid, Spain. We reviewed the clinical charts of patients who were admitted to hospital with a diagnosis of acute symptomatic PE as confirmed by Chest computed tomography from April 2008 to December 2011. Inclusion criteria were: patients older than 18 years with symptoms compatible with acute PE who were diagnosed with chest CT due to the presence of a filling defect that the attending radiologist felt it was consistent with an acute process. Patients were excluded if asymptomatic PE was incidentally diagnosed during evaluation for symptoms other than those mentioned above.

0735-6757/$ – see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2013.08.037

Methods

Table 1

Basal clinical characteristics and univariate analysis comparing groups 2 and 3 to group 1

We analyzed the records in terms of age, gender, prior medical history (chronic obstructive pulmonary disease, coronary artery		Group 1 (n= 290)	Group 2 (n= 94)	P	Group 3 (n= 52)	P
disease, congestive heart failure, diabetes mellitus, and active	Male gender (%)	51.4	49.4	.3	38.4	.06
smoking status), and accepted risk factors for PE (history of prior	Mean age (y)	67.3	71.5	.04	61.4	.2

venous thromboembolism, hypercoagulability condition, active ma-

lignancy, contraceptive pill use, recent immobilization or major

Risk factors for PE (%)

(13.7)

(15.2)

(12.4)

surgery within 30 days). We collected data on initial clinical

Active neoplasia 12.4 7.4 .1 15.3 .3

Recent major surgery 7.5 2.1 .04 3.7 .2

presentation such as blood pressure, heart rate, temperature,							Immobilization	19.3	10.6	.03	12.9	.3
presence of dyspnea, chest pain (centrothoracic, pleuritic or pleuro-							Previous DVT/PE	12.9	13.1	.4	11	.4
mechanic), cough, hemoptysis, fever, syncope, time of evolution of							oral contraceptives	3.4	5.3	.2	11.1	.2
symptoms, findings in chest X-ray, and electrocardiographic results. We also registered measurements related to PE severity (cardiac							Comorbidities (%) COPD Asthma	7.2 4.1	29.7 11.7	b.001 .01	13 3.7	.2 .6
biomarkers like plasma troponin I and D-dimer, right ventricular							Heart failure	3.1	8.5	.03	5.5	.2
function as observed on transthoracic echocardiography and the							Coronary artery disease	6.5	10.6	.1	11.1	.1
anatomic distribution of clots within the pulmonary vasculature on Active nicotine use 8.3 22.3 b.001 3.7 .2 chest CT). We also recorded mortality during hospitalization. Duration of symptoms (h) 107.3 152.2 .2 249.1 .002 (252.2) (299.1) (473.8)
Time to diagnosis was defined as the time (in hours) from first							Clinical presentation (%)
evaluation in the ED for that symptom to chest CT diagnosis. We							Dyspnea	72.9	84	.01	42.5	b.001
categorized each patient into one of three groups: group 1 (ED							Cough	13.4	35.1	b.001	25.9	.01
diagnosis), PE was diagnosed by chest CT that was ordered while the patient was still at the ED in the First visit; group 2, PE was diagnosed							Centrothoracic pain pleuritic chest pain Pleuromechanic pain	15.5 26.6 5.1	12 17 6.5	.2 .03 .3	9.2 22 29.6	.1 .3 b.001
by chest CT ordered during hospitalization after the patient had left							Syncope	15.1	3	.01	13	.4
the ED (the predefined study protocol required that all patients in this							Fever	5.1	13.8	.007	18.5	.002
group had to have one symptom consistent with PE written on the ED chart); and group 3, patients who were sent home with a wrong							Hemoptysis Electrocardiogram (%) Sinus tachycardia	3.3 26.5	2.1 40.6	.5 .01	12.9 28.6	.005 .4
alternative diagnosis and returned	to	the	ED	with	the	same	RBBB	15.1	16.8	.4	7.4	.1
complaints and were diagnosed of PE.							S1Q3T3	9.3	7.2	.3	0	.01
							Negative T waves	12.8	18	.2	9.2	.3

Analysis

The analysis compared the three mutually exclusive groups. Continuous variables were compared using Student t test and are presented as mean +- SD. Categorical variables were compared using ?² test or Fisher exact test and are expressed as absolute number and percentages. A univariate analysis was conducted to detect statistically significant differences in baseline demographic and clinical characteristics between patients depending on the presence of a delay in the diagnosis. Independent predictors for delayed diagnosis were evaluated by multivariate stepwise logistic regression analyses introducing clinically and statistically significant variables obtained in the univariate analysis. All statistical tests were 2-tailed and P b 0.05 was considered statistically significant throughout the study. Statistical analysis was performed using SPSS

14.1 (SPSS Inc, Chicago, IL). The study was approved by the local institutional review board.

Results

We retrospectively enrolled a total of 452 consecutive adult patients with acute PE who were admitted to hospital. We excluded 10 patients from the study because diagnosis was not performed with a chest CT as prespecified and 6 patients because PE did not have associated symptoms. Thus, 436 patients were finally included. Mean age was 67.4 +- 18.8 years. Two hundred twelve patients (48.6%) were male. One hundred forty-six patients (33.5%) had a delayed diagnosis of PE: 94 (21.5%) belong to group 2 (PE was diagnosed by chest CT ordered during hospitalization after the patient had left the ED) and 52 (11.9%) to group 3 (patients who were sent home with a wrong alternative diagnosis and returned to the ED with the same complaints and were diagnosed of PE). Demographics, risk factors for PE and clinical characteristics of patients are summarized in Table 1. Average time from first medical attention to diagnosis was

3.9 +- 3.2 hours, 56.6 +- 56 hours, and 180.3 +- 173 hours for groups

1, 2, and 3 respectively.

Chest x-ray (%)

Pulmonary infiltrate 11 24.4 .03 34 b.001

Atelectasis 6.1 9.5 .2 12.9 .08

Pleural effusion 18.1 18.6 .1 29.6 .07

Data are presented as mean +- SD unless otherwise indicated.

Group 1: pulmonary embolism was diagnosed by chest CT that was ordered while the patient was still in the emergency department in the first visit; group 2: pulmonary embolism was diagnosed by chest CT ordered during hospitalization after the patient had left the emergency department; group 3: patients who were sent home with a wrong alternative diagnosis and returned to the ED with the same complaints and were diagnosed of pulmonary embolism.

DVT/PE: Deep vein thrombosis/pulmonary embolism; COPD: Chronic obstructive pulmonary disease; RBBB: Right bundle branch block.

In the univariate analysis, patients from group 2 showed a statistically significant older age, a higher prevalence of chronic diseases, and a higher incidence of cough as clinical presentation as compared to patients from group 1. Patients from group 3 were significantly younger, with a higher proportion of pleuro-mechanical chest pain and hemoptysis on clinical presentation and with a higher proportion of patients with a pulmonary infiltrate on chest x-ray as compared to patients from group 1.

On the multivariate analysis we found that a history of chronic obstructive pulmonary disease (COPD) or asthma, the presence of cough, and the absence of syncope on clinical presentation were independent Clinical predictors of a delayed diagnosis in patients who were admitted to hospital (group 2). We also found that the absence of dyspnea, the presence of pleuro-mechanic thoracic pain, fever, hemoptysis and the presence of a pulmonary infiltrate on chest x-ray were independent predictors of a delayed diagnosis in patients who were sent home (group 3). Table 2 shows the results of the multivariate analysis.

The list of Alternative diagnoses performed by emergency physicians in groups 2 and 3 are listed in Table 3. Post hoc mean Geneva score of patients with an initial correct diagnosis of PE compared with patients with a delayed diagnosis who were admitted to hospital or who were sent home was 5.6 +- 3, 5.3 +- 2.6, and 4.8 +- 2.2, respectively. There were no statistically significant differences between groups.

Table 2

Logistic regression analysis showing independent predictors of a delayed diagnosis of pulmonary embolism

	Group 2
	Variables	OR	95% CI	P
	COPD	4.3	2.2-8.6	.00
	Asthma	3.4	1.2-9.7	.01
	Cough	2.5	1.4-4.7	.002
	Absence of Syncope	4.3	1.2-14.7	.02
	Group 3
	Variables	OR	95% CI	P
	Absence of dyspnea	2.3	1.1-4.8	.02
	Pleuro-mechanic pain	3.6	1.3-9.5	.01
	Fever	2.7	1.2-7.8	.04
	Hemoptysis	5	1.4-9-17.1	.009
	Pulmonary infiltrate	2.5	1.1-6.2	.04

OR, odds ratio; CI, confidence interval.

Group 2: pulmonary embolism was diagnosed by chest CT ordered during hospitalization after the patient had left the emergency department. Group 3: patients who were sent home with a wrong alternative diagnosis and returned to the ED with the same complaints and were diagnosed of pulmonary embolism.

Table 4

Comparison of data associated with pulmonary embolism severity comparing group 1 to group 2 and 3

	Group 1	Group 2	Group 3
Troponin I (ng/mL)a	0.26 (0.5)	0.22 (0.3)	0.1 (0.1)d
D-Dimer (ng/mL)b	7131 (8021)	8440 (7300)	4920 (7760) d
RVD on TTE (%)c	30	29.6	25.7
Chest CT clot location (%)
Proximal unilateral	16.9	23.9	17.6
Proximal bilateral	29	25.3	20.5
Distal unilateral	21.8	19.7	41.1d
Distal bilateral	32.1	30.9	20.5

Data are presented as mean +-SD unless otherwise indicated.

RVD, right ventricular dysfunction; TTE, transthoracic echocardiogram.

Group 1: Pulmonary embolism was diagnosed while the patient was still at the Emergency Department in the first visit. Group 2: pulmonary embolism was diagnosed by chest CT ordered during hospitalization after the patient had left the ED. Group 3: patients who were sent home with a wrong alternative diagnosis and returned to the ED with the same complaints and were diagnosed of pulmonary embolism.

^a n= 143 in group 1, 41 in group 2, and 17 in group 3.

^b n=256 in group 1, 63 in group 2, and 58 in group 3.

^c n= 190 in group1, 54 in group 2, and 28 in group 3.

^d P b .05 in univariate analysis.

Table 4 shows the results of different measurements to assess PE severity. Patients who were admitted to hospital (independently of delay in diagnosis) showed significantly higher levels of Troponin I and D-Dimer as compared to patients who were sent home. There were no between-groups statistically significant differences in right ventricular dysfunction detection, although transthoracic echocardio- gram was not performed in all patients. Participants who had a delayed diagnosis of PE had a very similar pattern of central-dominant clot distribution as compared to those in whom the diagnosis was made in the ED, except for patients who were sent home, who showed a higher prevalence of distal clot pattern.

A total of 21 patients (4.8%) died during hospitalization. Eleven patients (3.7%) from group 1, 5 patients (5.3%) from group 2, and 5 patients (9.2%) from group 3 died. There were no statistical differences between the 3 groups in mortality rates, although a trend toward a higher mortality rate was observed in group 3 as compared to groups 1 and 2 (P = .07). Analyzing the subgroup of patients who died, patients from group 3 were older (86.8 +- 5.8 years vs 64.3 +- 7.2 and 71.1 +- 8.5, from groups 1 and 2 respectively) and with a higher prevalence of active neoplasia (80%) and heart failure (60%) as compared to the other groups. The patient flowchart is summarized in Fig.

Discussion

We performed this study to learn more about patients who presented to the ED and were admitted or sent home without testing

Table 3

Wrong alternative Initial diagnosis in patients from group 2 and 3

	Group 2	Group 3
Initial diagnosis (%)
Pneumonia/RTI	34	41.3
Pleuritis	0	2.1
Mechanical chest pain	2.1	8.6
asthma exacerbation	2.1	4.3
Heart failure	15.3	6.5
COPD exacerbation	16.4	4.3
Angina/ACS	5.4	0
Others	19.7	32.6

RTI, respiratory tract infection. ACS, acute coronary syndrome.

Group 2: pulmonary embolism was diagnosed by chest CT ordered during hospitalization after the patient had left the emergency department. Group 3: patients who were sent home with a wrong alternative diagnosis and returned to the ED with the same complaints and were diagnosed of pulmonary embolism.

for PE but were later diagnosed of PE. We sought to measure how often this occurred and to test the hypothesis that patients with a delayed diagnosis of PE would exhibit several differences as compared to patients without a delay in both their clinical presentation profile and outcomes. Early diagnosis is essential to reduce the high morbidity and mortality associated with acute PE [9,10]. However, because symptoms and findings in PE are nonspecific, diagnosis is sometimes difficult at first presentation [11]. It is therefore essential for clinicians to recognize not only for risk factors for PE but also the clinical factors that may delay diagnosis.

In our study we found a significant percentage of patients (more than one third) with a delayed diagnosis of acute PE in the ED. Previous studies have shown a delayed diagnosis rate of 12% to 50%. These differences are mainly related to different criteria used for “delayed diagnosis” definition and to patient’s clinical characteristics. Some authors chose time from symptom onset (most of them 7 days) to define a delayed diagnosis [4,8]. Other reports used time of arrival at the ED (from 12 to 48 hours) rather than time from symptom onset to define “delayed diagnosis” [5,6]. Rodriguez et al defined delayed diagnosis as a non-suspected PE in the ED [12]. We chose this last criteria because we think that this is the definition which best describes the impact of overlooking acute PE.

Patients with a delayed diagnosis of PE who were admitted to hospital with a wrong diagnosis had a more complex clinical presentation than patients with ED-diagnosed PE with a lower rate of typical risk factors for PE like prior immobilization or recent surgery, a higher prevalence of prior cardiopulmonary disease (coronary artery disease, COPD, asthma or heart failure), and unspecific symptoms in this clinical scenario like dyspnea, cough, or fever that may facilitate a wrong initial diagnosis. These concomitant clinical features might have prompted clinicians to focus away from consideration of acute PE. We hypothesized and found that when patients present with well- known risk factors for PE, physicians are more likely to make an expedited diagnosis. Smith et al analyzed 400 patients with acute PE and found that patients with recent immobility and tachycardia had reduced times from arrival to diagnosis [6]. In the MASTER study, the presence of transient risk factors (recent surgery, severe medical diseases, immobilization, pregnancy) was found to be significantly associated with an earlier diagnosis [13]. Jimenez-Castro et al established early diagnoses in patients with surgical risk factors [14]. It is also a frequent situation that when patients with a history of cardiopulmonary disease present with an acute PE, clinicians commonly attribute their symptoms to their known cardiopulmonary disease rather than acute PE. In the previously mentioned study, Smith et al

Fig. Patient flowchart, groups, probability of PE and outcome. Group 1: pulmonary embolism was diagnosed while the patient was still at the ED in the first visit; group 2: pulmonary embolism was diagnosed during hospitalization after the patient had left the ED; group 3: patients who were sent home with a wrong alternative diagnosis and returned to the ED with the same complaints and were diagnosed of pulmonary embolism.

found that patients older than 65 years or with coronary artery disease and heart failure had significant longer times from arrival to diagnosis [6]. Pineda et al found that PE diagnosis was made less accurately in patients with coronary artery disease [15], and several studies found that PE may be diagnosed less accurately in patients with COPD [16-18]. Our results are in agreement with these previously published results.

Patients who were sent home with a wrong diagnosis and returned to the ED with the same complaints and were diagnosed of PE showed a typical profile concerning the following issues: (1) absence of risk factors for PE like younger age, less comorbidities, or the absence of a history of previous major surgery; (2) a clinical profile of distal PE without dyspnea and sharing symptoms and signs with other clinical situations like respiratory tract infection or mechanical chest pain, probably because pulmonary infarction pro- duces mechanical and pleuritic pain at the same time when visceral and parietal pleura are affected; (3) presence of a radiological infiltrate was an independent predictor of misdiagnosis. This might be related to the fact that pulmonary infarction might be confounded with a pneumonic infiltrate. To our knowledge, this is the first report that analyzes the clinical profile of patients who are sent home with a wrong diagnosis and are later diagnosed of PE.

We registered multiple biomarkers and imaging parameters associated with worsened outcome in all three groups (Troponin I and D-dimer plasma levels, right ventricular dysfunction in the echocardiogram and distribution of intrapulmonary clots) [5,19-25]. We found differences between patients who were admitted indepen- dently of delay as compared to patients who were sent home, who showed statistically significant lower mean values of Troponin I and D-dimer and a more frequent distal clot distribution. It is intuitive that patients who are discharged from the ED show a less Severe form of the disease. Kline et al showed that patients with a delayed diagnosis had PE of at least equal severity [5]. Rodriguez et al reported that a bilateral located clot was a protective factor for early diagnosis due to central PE have more intense clinical manifestations [12]. These results are consistent with ours.

We did not find significant differences in mortality between patients who were admitted to Hospital independently of time to diagnosis. We found a trend toward a higher mortality rate in patients who were sent home, although it did not reach statistical significance. In the subgroup of patients who were sent home with a wrong diagnosis and died during the subsequent admission, patients were older and showed a higher prevalence of associated coexisting conditions. Therefore, this higher mortality is probably related to these comorbidities and not to a delayed diagnosis. Most previous studies did not find association between delay and mortality [5,8,14,26].

Our study suffers from similar potential limitations of any retrospective analysis, although we believe that this approach was appropriate to identify patients who were sent home with a wrong diagnosis. We did not include the Wells score because a retrospective review of charts may not be sufficiently accurate for determining whether the clinicians felt that an alternative diagnosis was more or less likely than PE. There is a difference between doctors delay (the diagnosis of PE was not considered at presentation, or inadequate tests were performed to rule out acute PE) and a failure of the standardized diagnostic work-up of patients with suspected acute PE. Obviously, both conditions lead to Delayed diagnosis and treatment but have a distinct clinical significance. From the data provided by our study, it cannot be extracted which of both situations was relevant in the reported patients. We could not include patients who were sent home with a wrong diagnosis and died before they arrived at the hospital or patients who where attended in other hospitals not included in the study after an initial wrong diagnosis.

In conclusion, our study shows that delay in diagnosis of acute PE is frequent despite current diagnostic strategies. There are different types of clinical presentation depending on whether patients are sent home or admitted to hospital with a wrong diagnosis. However, delay in diagnosis is not an independent predictor of a more severe disease or death. These findings support the need for a high degree of vigilance for PE in this subgroup of patients, and clinicians should be aware of these factors to provide expedited management of acute PE.

Acknowledgments

We acknowledge Carlos Mingo Rodriguez, MD (Infanta Cristina University Hospital), for his advice and support and Belen Gonzalez- Herrero and Sergio Garcia-Ramos (Complutense University medical students) for collecting data.

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