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An Emergency Department Guideline for the Diagnosis of Pulmonary Embolism: An Outcome Study Michael D. Brown, MD, MSc, Steven J. Vance, MD, Jeffery A. Kline, MD Abstract Objective: To assess the clinical outcome of patients suspected of pulmonary embolism (PE) following implementation of an emergency department (ED) diagnostic guideline. Methods: A prospective observational study of all patients suspected of PE who presented to the ED during a four-month study period. The authors’ modification of the Charlotte criteria recommended D-dimer testing in those younger than 70 years of age with a low clinical suspicion of PE and no unexplained hypoxemia, unilateral leg swelling, recent surgery, hemoptysis, pregnancy, or prolonged duration of symptoms. The primary outcome was the identification of venous thromboembolism during a three-month follow-up period. The negative predictive value of the overall diagnostic strategy and the test characteristics of D-dimer were calculated. Results: A total of 1,207 consecutive patients were evaluated for suspected PE; 71 (5.8%) were diagnosed
with venous thromboembolism. One missed case of PE was identified on follow-up, yielding a negative predictive value of 99.9% (95% confidence interval [CI] = 99.5% to 100%). The missed case was a patient who presented with pleuritic chest pain and shortness of breath; a chest radiograph revealed pneumothorax, and the physician decided not to pursue the positive D-dimer result. The patient returned six weeks later with PE. Subgroup analysis of patients having D-dimer performed (n = 677) yields a sensitivity of 0.93 (95% CI = 0.77 to 0.98) and a specificity of 0.74 (95% CI = 0.70 to 0.77). Conclusions: Implementation of a PE diagnostic guideline in a community ED setting is safe and has improved the specificity of the enzyme-linked immunosorbent assay D-dimer test when compared with previous studies. Key words: pulmonary embolism; diagnosis; guideline. ACADEMIC EMERGENCY MEDICINE 2005; 12:20–25.
The evaluation of patients suspected of pulmonary embolism (PE) is complex, and numerous diagnostic strategies have been suggested.1–7 Clinical guidelines or protocols may assist physicians with complicated diagnostic algorithms and improve care by decreasing inappropriate variance in practice style.8,9 At the same time, algorithms that reduce patient care into a sequence of binary decisions often do injustice to the complexity of medicine.10 The rationale for a PE ruleout protocol has been described; however, the safety and efficiency of a PE rule-out protocol awaits empiric confirmation.11,12 Generally, simple innovations spread faster than complicated ones.13 A prediction rule will be used if it makes clinical sense and is simple.14 One of the aims of our PE diagnostic guideline was to simplify the complicated algorithms and decision rules that have
been proposed.1 The guideline focus was on pretest probability assessment and the appropriate use of D-dimer testing.7,8,12 The implementation of a PE ruleout protocol or guideline requires the understanding and approval of physicians at the local level. The emergency physicians at our institution agreed to start with empiric clinical judgment to arrive at a pretest probability for PE and then apply a modification of the Charlotte criteria to assist in diagnostic decision making.7,15 This provided shape and structure to our clinical judgment yet maintained the decision-making flexibility that is often required when applying rules to the individual patient.16 For a PE rule-out protocol to be considered safe, it has been recommended that the posttest probability of a negative workup be ,1%12 or that the upper 95% confidence limit be ,3%.1 There has been a call for increased implementation research and, more specifically, the evaluation of diagnostic strategies in practice.17 The primary objective of our study was to determine the safety of a PE diagnostic guideline in the emergency department (ED) setting based on the number of cases of missed PE identified over a three-month follow-up period. A secondary objective was to assess the efficiency of the guideline by determining the test performance of D-dimer in the low-risk subgroup and the rate of negative formal imaging for PE after implementation of our PE rule-out protocol.
From the Grand Rapids MERC/Michigan State University Program in Emergency Medicine (MDB, SJV), Grand Rapids, MI; and Department of Emergency Medicine, Carolinas Medical Center (JAK), Charlotte, NC. Received May 3, 2004; revision received July 24, 2004; accepted August 2, 2004. Supported in part by K-30 award #HL04113 from National Heart, Lung, and Blood Institute. Address for correspondence: Michael D. Brown, MD, MSc, Spectrum Health—Butterworth, Emergency Medicine, 100 Michigan Avenue NE, Grand Rapids, MI 49503. Fax: 616-391-3674; e-mail:
[email protected]. doi:10.1197/j.aem.2004.08.046
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METHODS Study Design. This prospective observational study assessed the clinical outcome of patients suspected of PE following implementation of an ED diagnostic guideline. The guideline was introduced and approved by the Department of Emergency Medicine five months before initiation of the study. To encourage appropriate use of the enzyme-linked immunosorbent assay (ELISA) D-dimer as outlined in the guideline, the summary (Table 1) was embedded in the software of the electronic medical record and showed as a ‘‘pop-up’’ on the order entry screen whenever a physician ordered a D-dimer test.9,18 Physicians were also encouraged to utilize a simple worksheet that included a summary flow diagram and the following questions: 1) Does the patient typically seek care at Spectrum Health? 2) What is the pretest probability for PE: low (,20%), intermediate, or high? The hospital’s institutional review board approved the observational study and required written or verbal informed consent for follow-up contact only. Study Setting and Population. The study was conducted at two community EDs with a combined annual ED census of approximately 130,000 in 2003. Spectrum Health—Butterworth is an urban teaching hospital with 30 emergency medicine residents and 31 full-time attending physicians. Spectrum Health— Blodgett is an affiliated suburban hospital without an emergency medicine residency program and 15 full-time attending physicians. Patients were enrolled for 15 weeks, from May 21 to August 28, 2003. The study population consisted of a consecutive sample of adult patients (18 years or older) presenting to the ED with clinical suspicion of acute PE. Patients were identified either by completion of a PE worksheet by the emergency physician or by research staff using the electronic medical record to identify all patients having had a diagnostic test for PE during each week of the study period. Diagnostic tests queried on the electronic medical record included all ED patients having had a D-dimer test, computerized tomography (CT) pulmonary angiography, combined CT venography and pulmonary angiography (CTVPA), ventilation-perfusion scintillation lung scan, or pulmonary
TABLE 1. Summary of Diagnostic Guideline for Appropriate Use of D-dimer Testing D-dimer testing not recommended if any one of the following: Unexplained hypoxia (pulse oximetry ,95%) Unilateral leg swelling Recent surgery (within past four weeks) Hemoptysis Pregnancy Age 70 years or older Duration of symptoms $4 days
21 angiography. All potential patients identified in the electronic medical record screen performed by the research staff were reviewed by one of the investigators (SJV) to confirm that these patients were eligible for study enrollment (clinical suspicion for PE). Study Protocol. The Charlotte criteria are based on a set of predictors derived from a typical outpatient ED population.15 We used a modification of this rule (Table 1) that retained the four strongest predictors, because in a derivation population it was found that the presence of any one of these predictors increased the pretest probability of PE into the moderate to high range. Other modifications were based on the desire to minimize false-positive D-dimer test results. Prior work has shown that elder patients often have comorbidities that result in a significant decrease in the specificity of the D-dimer test to an unacceptably low level (14%–17%).19–21 Receiver operating characteristic curve analysis on age in the original database for the Charlotte criteria indicated a minimal change in the likelihood ratio negative with adjustment of age from 50 to 70 years. Moreover, prior work has shown that approximately 75% of all healthy, pregnant women have a D-dimer level above the traditional cutoff of 500 ng/mL.22 Accordingly, we modified the Charlotte rule such that patients aged 70 years or older and pregnant patients were ineligible for D-dimer testing. Because we were concerned about a possible decrease in sensitivity of the D-dimer with prolonged duration of symptoms, patients with symptoms present for $4 days were also considered ineligible for D-dimer testing.21 According to the diagnostic guideline, all adult patients presenting with suspicion for PE were first stratified into low (, 20%) or moderate to high pretest probability risk groups using the empiric clinical judgment of the treating physician. The guideline recommended that patients with moderate to high probability of PE undergo diagnostic imaging to assess for suspected PE without obtaining a D-dimer level. D-dimer testing was recommended for patients with low probability for PE as determined by the empiric judgment of the treating physician. However, if any of the following criteria were present, the guideline suggested that the patient was ineligible for D-dimer testing: unexplained hypoxia (pulse oximetry ,95%), unilateral leg swelling, surgery within the past four weeks, hemoptysis, pregnancy, age 70 years or older, or duration of symptoms $4 days (Table 1). Diagnostic imaging was recommended for patients having a positive D-dimer (ELISA D-dimer $500 ng/mL). Due to the wide range of reported sensitivity of CT angiography23–25 and the uncertain significance of a missed subsegmental PE,26 the guideline suggested CTVPA as the imaging modality of choice.27,28 However, CTVPA was not recommended in patients with renal insufficiency, pregnancy, or allergy to iodinated contrast dye.6 In
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such cases, the guideline suggested that the treating physician consult with the radiologist regarding imaging alternatives.
dialysis), hospice care, and absence of a ‘‘do not resuscitate’’ order. The objective was a 99% negative predictive value (1% false-negative rate).
Measurements. Although a positive pulmonary angiogram or autopsy has historically been the reference standard for the diagnosis of PE, we considered any one of the following as acceptable surrogate reference standards: 1) CT or pulmonary angiography positive for PE, 2) lower extremity imaging (Doppler ultrasonography or CT venography) positive for deep vein thrombosis, 3) high probability ventilation-perfusion scintillation lung scan, or 4) death secondary to venous thromboembolism. Similar to most contemporary PE studies, the absence of a thromboembolic event over a minimum of three months was considered the reference standard for ruling out PE.1,29–31 Following a negative ED workup for PE, research staff ascertained the occurrence of venous thromboembolism over the following three months by searching the electronic medical record and completing a data collection form on all subjects. Although the electronic medical record was used as the primary source for follow-up on all patients, for those patients who did not confirm with the emergency physician that they routinely utilize the Spectrum Health system for their health care needs, a member of the research staff attempted scripted telephone follow-up after three months to determine if they had been diagnosed with venous thromboembolism since the time of ED discharge. If contact by telephone was unsuccessful after three attempts on different days, a questionnaire was sent via U.S. mail. Kent County medical examiner records were searched for matches for all enrolled subjects over the three-month follow-up period. In addition, if both telephone and mail follow-up attempts were unsuccessful, a search of the social security death index was performed. Data were entered into Microsoft Access 2000 (Microsoft Corp., Redmond, WA).
Data Analysis. The negative predictive value of the diagnostic guideline was calculated as the number of patients with a negative workup for PE in the ED and no evidence of thromboembolism on follow-up (true negatives) divided by the total number of patients with a negative ED workup (true negatives and false negatives). Statistical analysis was performed using simple proportions with 95% confidence intervals (CIs) where appropriate. Statistical tests were performed using the SAS statistical application program (version 8.0; SAS Institute Inc., Cary, NC) and Confidence Interval Analysis (version 2.0; University of Southampton, Southampton, England). The sample size was calculated based on an estimated negative predictive value of 99.5% with a 95% CI width of 0.8. In order to obtain a 95% CI of 99.1% to 99.9% for the negative predictive value, we estimated that a total sample size of 1,193 subjects would be required based on an estimated PE prevalence of 20%.
Primary Outcome Measurement. The primary outcome was the negative predictive value of the protocol. Any patient diagnosed as having venous thromboembolism (deep vein thrombosis or PE) in the three-month period following a negative ED evaluation for PE was considered a missed PE (falsenegative workup). Because the exact cause of death is often uncertain when an autopsy is not performed, we calculated the results on a ‘‘worst-case’’ scenario basis, which assumes all unexpected deaths of unknown cause to be secondary to PE. An unexpected death of uncertain cause was defined as a patient younger than 90 years of age with absence of a clear alternative mechanism of death (e.g., trauma, septic shock, intracranial hemorrhage), a defined end-stage disease being treated with comfort care only (e.g., metastatic cancer, end-stage renal failure with withdrawal of
RESULTS Characteristics of Study Subjects. The study cohort included 1,207 patients with a mean age of 48 years (range, 18–96 years) and a 2:1 female predominance (n = 792). Seventy-one (5.8%) were diagnosed with venous thromboembolism; 70 were diagnosed with PE during the initial ED visit, and one missed case was identified at three-month follow-up. The 1,137 patients with a negative ED evaluation had three-month follow-up performed using the electronic medical record. In addition, three-month telephone or mail contact was attempted on 896 patients who were not confirmed by the treating emergency physician as routinely seeking care through the Spectrum Health system; telephone or mail follow-up was successful in 52%. In those discharged from the ED following a negative workup, follow-up confirmed 22 deaths; no deaths were directly attributable to PE. The diagnostic testing strategy used by the treating physicians is summarized in Figure 1. Main Results. Following implementation of the ED diagnostic guideline, the overall miss rate was 0.1% (1/1,137), resulting in a negative predictive value of 99.9% (95% CI = 99.5% to 100%). The only definitively confirmed missed case was a 48-year-old man with a history of spontaneous pneumothorax and PE who presented with sudden onset of pleuritic chest pain associated with shortness of breath and hypoxia. Examination revealed tachycardia and decreased breath sounds on the left. The treating physician had marked ‘‘intermediate pretest probability’’ on the
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Figure 1. Flow diagram of diagnostic testing performed on the study population. Pos = positive for venous thromboembolism.
worksheet yet ordered a D-dimer test anyway. The D-dimer level was elevated at 524 ng/mL; however, the chest radiograph confirmed a pneumothorax. The physician did not pursue the positive D-dimer result and marked on the worksheet that the guideline was not followed; arrangements were made for chest tube placement and admission. The patient returned to the ED six weeks later with chest pain and shortness of breath. D-dimer level on the return visit was .1,000 ng/mL, and CT angiography demonstrated PE. The prevalence of PE among those patients who went directly to diagnostic imaging (n = 530) was 8.3%. In contrast, the prevalence of PE among those patients having had a D-dimer test performed (n = 677) was 4.0%. In this low-risk subgroup, the ELISA D-dimer had a sensitivity of 0.93 (95% CI = 0.77 to 0.98) and a specificity of 0.74 (95% CI = 0.70 to 0.77). False-positive D-dimer results subjected 148 patients to further radiologic investigation. In 442 cases, the D-dimer level was normal and the physician followed the diagnostic guideline recommendations and ordered no further imaging studies. However, in 40 cases, the clinician pursued further radiographic testing after a negative D-dimer result and PE was diagnosed in two (5%). The two patients with falsenegative D-dimer results were diagnosed with PE during the initial ED evaluation despite an ELISA D-dimer result ,500 ng/mL. Interestingly, both patients had a ‘‘high’’ normal result (462 and 476 ng/mL) and the physician in each case decided to further pursue the diagnosis with imaging. One patient was morbidly obese and complained of shortness of breath for three weeks with a sudden worsening of symptoms on the day of presentation; the treating physician marked ‘‘low pretest probability’’ on the worksheet and stated that he followed the guideline. The second patient was a quadriplegic with a past history of thromboembolic disease; a worksheet was not completed. Of the 1,207 patients who presented with suspected PE, a total of 739 patients had at least one imaging study performed (Figure 1) in the ED and 9.5% were
positive for venous thromboembolism. There were 468 patients (39%) screened for PE who did not have any radiologic evaluation for venous thromboembolism.
DISCUSSION Innovations are often more robust to modification than their inventors believe, and local adaptation, which often involves simplification, is nearly a universal property of successful dissemination.13 Our ED diagnostic guideline attempted to simplify the complicated ED evaluation for suspected PE using clinical gestalt as the starting point, followed by application of a modified clinical prediction rule.15 This simple approach, along with computerized clinical decision support, encouraged consistent application of the guideline.7,18 The use of any PE rule-out protocol depends not only on the accuracy of the strategy but also on the feasibility, including local resources and practice patterns.1 Few investigators have reported results on a consecutive sample of patients suspected of PE following implementation of an overall ED diagnostic strategy.32–34 Chagnon et al. used a decision rule that has reduced applicability as an immediate, bedside tool because it requires the results of arterial blood gases and chest radiography.34,35 The outcome study by Dunn et al. did not utilize follow-up in the analysis.33 Our outcome study demonstrated that in a community ED setting, the adopted diagnostic guideline was both feasible and safe. The availability of simple screening tests such as D-dimer encourage physicians to initiate a diagnostic evaluation for suspected PE when in the past this diagnosis may have been dismissed on the basis of the history and physical examination alone. The proportion of patients suspected of PE in whom the diagnosis is confirmed has steadily decreased over the past two decades.11 This decreasing prevalence is probably a result of increased awareness of atypical presentations of thromboembolic disease and the availability of screening tests such as D-dimer.11 Canadian researchers performed a multicenter study of outpatients
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suspected of PE and reported a prevalence of 9%.36 The lower prevalence of PE (6%) in our study population confirms this trend and may reflect physician concern for malpractice litigation in the United States. Our prevalence was similar to that in an EDbased study that assessed the efficiency and effectiveness of using D-dimer testing as a screening test for PE.33 If physicians are now ordering D-dimer tests on patients with a very low pretest probability, which inevitably results in some false-positive results, it must be questioned whether these subjects with very low suspicion for PE are being exposed to unnecessary radiologic studies. It has been suggested that at least 50% of patients screened with D-dimer testing must have a negative result in order to avoid increased utilization of radiographic imaging.12 Of the total number of D-dimer tests obtained in our study population, 71% were negative. Use of the guideline improved the specificity of the ELISA D-dimer test when compared with previously reported studies.19 We believe that use of our diagnostic guideline would have had a similar effect on the test characteristics of a turbidimetric D-dimer test.37,38
LIMITATIONS The primary objective of this study was to evaluate the safety of an ED diagnostic guideline for PE. Due to incorporation bias, the classic test characteristics (i.e., sensitivity, specificity) of the overall guideline cannot be accurately assessed because portions of the diagnostic guideline were also considered the criterion standard for identifying the presence of venous thromboembolism (i.e., false-positive diagnostic imaging could not be ascertained). A secondary objective was to determine if use of the guideline would improve D-dimer test performance. Thus, the results of this subgroup analysis must be interpreted and applied with caution because selection bias was intentionally introduced within the guideline. The test characteristics of the ELISA D-dimer reported in this study should only be applied to a restricted lowrisk patient population as described. If a clinical decision support instrument is to be successful, physicians must be allowed to exercise their clinical judgment and override the guideline recommendations.18 There were 20 instances in which the physician ordered a D-dimer test in patients 70 years of age or older. As expected, the specificity among this elder subgroup was very low at 26%. We identified a number of cases in which the physician ordered a D-dimer test and then chose to disregard the result; an imaging study was ordered on 40 patients despite a negative D-dimer result. To order a diagnostic study and then discard the result would appear to be a waste of health care resources. However, the guideline allowed for flexibility with application to the individual patient; this explains how two patients with
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false-negative D-dimer results were diagnosed with PE in the ED. It may be argued that these two patients should have gone directly to imaging without D-dimer testing because both had risk factors for PE (morbid obesity and immobility). However, these are examples of traditional, population-based risk factors associated with venous thromboembolism that may influence clinical decision making on the individual patient yet may not be strong enough predictors in databases derived from ED patients to incorporate into a prediction rule.39 Ideally, all patients suspected of PE would have had an estimate of pretest probability documented. The investigators had discussed the possibility of creating a system whereby the entry of an order for a D-dimer test or a radiologic imaging study for PE would not be processed without a completed pretest probability estimate on an electronic form. This option was met with resistance by the local clinicians and was viewed as obstructing physician efficiency and patient flow. Instead, physicians were ‘‘encouraged’’ to complete a pretest probability assessment form. The compliance with this approach was too low to be of any use in the analysis. Performing three-month follow-up using the electronic medical record was very efficient and accurate. Telephone follow-up was resource intensive with very low yield. Investigators performing followup for outcome studies or quality assurance audits should consider using the electronic medical record as a reliable and efficient source of data. Our modifications to the Charlotte rule could be reconsidered. The decision to exclude patients for prolonged duration of symptoms was based on indicative rather than conclusive evidence.21,40 Our secondary analysis did not show additional benefit to including this term in the screening process.
CONCLUSIONS Clinical guidelines have the potential to improve health outcomes and reduce costs. However, the best care for the majority of patients, as recommended in the guideline, may be inappropriate for the individual patient.10 Physicians must continue to use good clinical judgment when deciding to follow any guideline.8 This outcome study has demonstrated that implementation of a PE diagnostic guideline in a community hospital ED is safe and efficient. The authors thank Jan Anderson, RN, Jennifer Kolenda, BA, Nikalus Sheridan, and Laurel Viewig, BS, for assistance with data management and Thomas Summerfelt, PhD, and Steve Korzeniewski, BA, for assistance with statistical analysis.
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