D. Mark Courtney

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

CONTEXT The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. OBJECTIVE To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. DATA SOURCES A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). STUDY SELECTION Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. DATA EXTRACTION Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. DATA SYNTHESIS Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Incidence and Predictors of Repeated Computed Tomographic Pulmonary Angiography in Emergency Department Patients

STUDY OBJECTIVE Use of contrast-enhanced computed tomography (CT) of the pulmonary arteries to evaluate for pulmonary embolism has increased, raising concern about radiation and contrast toxicity. We sought to measure the frequency of repeat CT pulmonary angiography in emergency department (ED) patients. METHODS This was a prospective, longitudinal follow-up of ED patients who underwent first-time CT pulmonary angiography as part of a research protocol for diagnosis of pulmonary embolism in 2001 to 2002. Two authors (DMB and MCK) searched electronic medical record databases to measure the frequency of repeated CT scans performed within 5 years. Primary outcome was greater than or equal to 1 repeated CT pulmonary angiography examination. Radiologist-written interpretations of CT pulmonary angiography were categorized by 2 observers (DMB and JAK). Cox regression was used to estimate hazard ratios for 24 clinical variables. RESULTS A cohort of 675 ED patients was observed for a median of 1,989 days: 226 of 675 (33%) had at least 1 additional CT pulmonary angiography scan, and 60 died with no repeated CT pulmonary angiography, leading to a mortality-adjusted frequency of repeated CT pulmonary angiography scanning of 226 of 615, or 37%. Seventy-three percent of the cohort had 1 or more subsequent CT scans of any body part, and 31 patients (5%) had 5 or more repeated CT pulmonary angiography scans. The pulmonary embolism (positive) prevalence was 57 of 675 (8.4%; 95% confidence interval [CI] 6.5% to 10.8%) on the first CT pulmonary angiography versus 8 of 226 (3.5%; 95% CI 1.5% to 6.9%) on the second CT pulmonary angiography scan. Hazard ratios indicated that respiratory rate, active malignancy, previous coronary artery disease, and previous or new diagnosis of venous thromboembolism were positively associated with repeated CT pulmonary angiography scanning. CONCLUSION At least one third of ED patients who undergo CT pulmonary angiography scanning will have a second CT pulmonary angiography result that will be negative for pulmonary embolism. New methods are needed to exclude pulmonary embolism recurrence without use of ionizing radiation.

High discordance of chest x-ray and computed tomography for detection of pulmonary opacities in ED patients: implications for diagnosing pneumonia ☆

OBJECTIVE To evaluate the diagnostic performance of chest x-ray (CXR) compared to computed tomography (CT) for detection of pulmonary opacities in adult emergency department (ED) patients. METHODS We conducted an observational cross-sectional study of adult patients presenting to 12 EDs in the United States from July 1, 2003, through November 30, 2006, who underwent both CXR and chest CT for routine clinical care. CXRs and CT scans performed on the same patient were matched. CXRs and CT scans were interpreted by attending radiologists and classified as containing pulmonary opacities if the final radiologist report noted opacity, infiltrate, consolidation, pneumonia, or bronchopneumonia. Using CT as a criterion standard, the diagnostic test characteristics of CXR to detect pulmonary opacities were calculated. RESULTS The study cohort included 3423 patients. Shortness of breath, chest pain and cough were the most common complaints, with 96.1% of subjects reporting at least one of these symptoms. Pulmonary opacities were visualized on 309 (9.0%) CXRs and 191 (5.6 %) CT scans. CXR test characteristics for detection of pulmonary opacities included: sensitivity 43.5% (95% CI, 36.4%-50.8%); specificity 93.0% (95% CI, 92.1%-93.9%); positive predictive value 26.9% (95% CI, 22.1%-32.2%); and negative predictive value 96.5% (95% CI, 95.8%-97.1%). CONCLUSION In this multicenter cohort of adult ED patients with acute cardiopulmonary symptoms, CXR demonstrated poor sensitivity and positive predictive value for detecting pulmonary opacities. Reliance on CXR to identify pneumonia may lead to significant rates of misdiagnosis.

Factors Associated With Positive D-dimer Results in Patients Evaluated for Pulmonary Embolism

OBJECTIVES Available D-dimer assays have low specificity and may increase radiographic testing for pulmonary embolism (PE). To help clinicians better target testing, this study sought to quantify the effect of risk factors for a positive quantitative D-dimer in patients evaluated for PE. METHODS This was a prospective, multicenter, observational study. Emergency department (ED) patients evaluated for PE with a quantitative D-dimer were eligible for inclusion. The main outcome of interest was a positive D-dimer. Odds ratio (ORs) and 95% confidence intervals (CIs) were determined by multivariable logistic regression. Adjusted estimates of relative risk were also calculated. RESULTS A total of 4,346 patients had D-dimer testing, of whom 2,930 (67%) were women. A total of 2,500 (57%) were white, 1,474 (34%) were black or African American, 238 (6%) were Hispanic, and 144 (3%) were of other race or ethnicity. The mean (+/-SD) age was 48 (+/-17) years. Overall, 1,903 (44%) D-dimers were positive. Model fit was adequate (c-statistic = 0.739, Hosmer and Lemeshow p-value = 0.13). Significant positive predictors of D-dimer positive included female sex; increasing age; black (vs. white) race; cocaine use; general, limb, or neurologic immobility; hemoptysis; hemodialysis; active malignancy; rheumatoid arthritis; lupus; sickle cell disease; prior venous thromboembolism (VTE; not under treatment); pregnancy and postpartum state; and abdominal, chest, orthopedic, or other surgery. Warfarin use was protective. In contrast, several variables known to be associated with PE were not associated with positive D-dimer results: body mass index (BMI), estrogen use, family history of PE, (inactive) malignancy, thrombophilia, trauma within 4 weeks, travel, and prior VTE (under treatment). CONCLUSIONS Many factors are associated with a positive D-dimer test. The effect of these factors on the usefulness of the test should be considered prior to ordering a D-dimer.

Evaluation of Pulmonary Embolism in the Emergency Department and Consistency With a National Quality Measure: Quantifying the opportunity for improvement

BACKGROUND The National Quality Forum (NQF) has endorsed a performance measure designed to increase imaging efficiency for the evaluation of pulmonary embolism (PE) in the emergency department (ED). To our knowledge, no published data have examined the effect of patient-level predictors on performance. METHODS To quantify the prevalence of avoidable imaging in ED patients with suspected PE, we performed a prospective, multicenter observational study of ED patients evaluated for PE from 2004 through 2007 at 11 US EDs. Adult patients tested for PE were enrolled, with data collected in a standardized instrument. The primary outcome was the proportion of imaging that was potentially avoidable according to the NQF measure. Avoidable imaging was defined as imaging in a patient with low pretest probability for PE, who either did not have a D-dimer test ordered or who had a negative D-dimer test result. We performed subanalyses testing alternative pretest probability cutoffs and imaging definitions on measure performance as well as a secondary analysis to identify factors associated with inappropriate imaging. χ(2) Test was used for bivariate analysis of categorical variables and multivariable logistic regression for the secondary analysis. RESULTS We enrolled 5940 patients, of whom 4113 (69%) had low pretest probability of PE. Imaging was performed in 2238 low-risk patients (38%), of whom 811 had no D-dimer testing, and 394 had negative D-dimer test results. Imaging was avoidable, according to the NQF measure, in 1205 patients (32%; 95% CI, 31%-34%). Avoidable imaging owing to not ordering a D-dimer test was associated with age (odds ratio [OR], 1.15 per decade; 95% CI, 1.10-1.21). Avoidable imaging owing to imaging after a negative D-dimer test result was associated with inactive malignant disease (OR, 1.66; 95% CI, 1.11-2.49). CONCLUSIONS One-third of imaging performed for suspected PE may be categorized as avoidable. Improving adherence to established diagnostic protocols is likely to result in significantly fewer patients receiving unnecessary irradiation and substantial savings.

Use of pulse oximetry to predict in-hospital complications in normotensive patients with pulmonary embolism

PURPOSE A simple method is needed to risk stratify normotensive patients with pulmonary embolism. We studied whether bedside clinical data can predict in-hospital complications from pulmonary embolism. METHODS We performed a multicenter derivation phase, followed by validation in a single center. All patients were normotensive; the diagnosis of pulmonary embolism was established by objective imaging. Classification and regression analysis was performed to derive a decision tree from 27 parameters recorded from 207 patients. The validation study was conducted on a separate group of 96 patients to determine the derived criterions diagnostic accuracy for in-hospital complications (cardiogenic shock, respiratory failure, or death). RESULTS Mortality in the derivation phase was 4% (n = 8) at 24 hours and 10% (n = 21) at 30 days. A room-air pulse oximetry reading <95% was the most important predictor of death; mortality was 2% (95% confidence interval [CI]: 0% to 6%) in patients with pulse oximetry >or=95% versus 20% (95% CI: 12% to 29%) with pulse oximetry <95%. In the validation phase, the room-air pulse oximetry was <95% at the time of diagnosis in 9 of 10 patients who developed an in-hospital complication (sensitivity, 90%) and >or=95% in 55 of 86 patients without complications (specificity, 64%). CONCLUSION Mortality from pulmonary embolism in normotensive patients is high. A room-air pulse oximetry reading >or=95% at diagnosis is associated with a significantly lower probability of in-hospital complications from pulmonary embolism.

Clinical features from the history and physical examination that predict the presence or absence of pulmonary embolism in symptomatic emergency department patients: Results of a prospective, multicenter study

STUDY OBJECTIVE Prediction rules for pulmonary embolism use variables explicitly shown to estimate the probability of pulmonary embolism. However, clinicians often use variables that have not been similarly validated, yet are implicitly believed to modify probability of pulmonary embolism. The objective of this study is to measure the predictive value of 13 implicit variables. METHODS Patients were enrolled in a prospective cohort study from 12 centers in the United States; all had an objective test for pulmonary embolism (D-dimer, computed tomographic angiography, or ventilation-perfusion scan). Clinical features including 12 predefined previously validated (explicit) variables and 13 variables not part of existing prediction rules (implicit) were prospectively recorded at presentation. The primary outcome was venous thromboembolism (pulmonary embolism or deep venous thrombosis), diagnosed by imaging up to 45 days after enrollment. Variables with adjusted odds ratios from logistic regression with 95% confidence intervals not crossing unity were considered significant. RESULTS Seven thousand nine hundred forty patients (7.2% venous thromboembolism positive) were enrolled. Mean age was 49 years (standard deviation 17 years) and 67% were female patients. Eight of 13 implicit variables were significantly associated with venous thromboembolism; those with an adjusted odds ratio (OR) greater than 1.5 included non-cancer-related thrombophilia (OR 1.99), pleuritic chest pain (OR 1.53), and family history of venous thromboembolism (OR 1.51). Implicit variables that predicted no venous thromboembolism outcome included substernal chest pain, female sex, and smoking. Nine of 12 explicit variables predicted a positive outcome of venous thromboembolism, including patient history of pulmonary embolism or deep venous thrombosis in the past, unilateral leg swelling, recent surgery, estrogen, hypoxemia, and active malignancy. CONCLUSION In symptomatic outpatients being considered for possible pulmonary embolism, non-cancer-related thrombophilia, pleuritic chest pain, and family history of venous thromboembolism increase probability of pulmonary embolism or deep venous thrombosis. Other variables that are part of existing pretest probability systems were validated as important predictors in this diverse sample of US emergency department patients.

Point-of-care ultrasonography by pediatric emergency medicine physicians

Emergency physicians have used point-of-care ultrasonography since the 1990s. Pediatric emergency medicine physicians have more recently adopted this technology. Point-of-care ultrasonography is used for various scenarios, particularly the evaluation of soft tissue infections or blunt abdominal trauma and procedural guidance. To date, there are no published statements from national organizations specifically for pediatric emergency physicians describing the incorporation of point-of-care ultrasonography into their practice. This document outlines how pediatric emergency departments may establish a formal point-of-care ultrasonography program. This task includes appointing leaders with expertise in point-of-care ultrasonography, effectively training and credentialing physicians in the department, and providing ongoing quality assurance reviews.

The rapid and progressive degeneration of the cervical multifi dus in whiplash: An MRI study of fatty infi ltration

Study Design. Single-center prospective longitudinal study. Objective. To study the (1) temporal development of muscle fatty infiltrates (MFI) in the cervical multifidi after whiplash, (2) differences in multifidi MFI between those who recover or report milder pain–related disability and those who report moderate/severe symptoms at 3 months, and (3) predictive value of multifidi MFI outcomes. Summary of Background Data. The temporal development of MFI on conventional magnetic resonance image has been shown to be associated with specific aspects of pain and psychological factors. The replication of such findings has yet to be explored longitudinally. Methods. Thirty-six subjects with whiplash injury were enrolled at less than 1 week postinjury and classified at 3 months using percentage scores on the Neck Disability Index as recovered/mild (0%–28%) or severe (≥30%). A fat/water magnetic resonance imaging measure, patient self-report of pain-related disability, and post-traumatic stress disorder were collected at less than 1 week, 2 weeks, and 3 months postinjury. The effects of time and group (per Neck Disability Index) and the interaction of time by group on MFI were determined. Receiver operating characteristic curve analysis was used to determine a cut-point for MFI at 2 weeks to predict outcome at 3 months. Results. There was no difference in MFI across groups at enrolment. MFI values were significantly higher in the severe group than those in the recovered/mild group at 2 weeks and 3 months. The receiver operating characteristic curve analysis indicated that MFI levels of 20.5% or above resulted in a sensitivity of 87.5% and a specificity of 92.9% for predicting outcome at 3 months. Conclusion. Consistent with previous evidence, muscle degeneration occurs soon after injury but only in those patients with poor functional recovery. This study provides further evidence that (1) multifidi MFI occur in tandem with known predictive risk factors (older age, pain-related disability, and post-traumatic stress disorder) and (2) routine imaging protocols may need to be reconsidered in the vast majority of patients after whiplash. Level of Evidence: 3

Risk of Thromboembolism Varies, Depending on Category of Immobility in Outpatients

STUDY OBJECTIVE Immobility predisposes to venous thromboembolism, but this risk may vary, depending on the underlying cause of immobility. METHODS This was a prospective, longitudinal outcome study of self-presenting emergency department (ED) patients who were from 12 hospitals and had suspected venous thromboembolism. Using explicit written criteria, clinicians recorded clinical features of each patient in the ED by using a Web-based data form. The form required one of 6 types of immobility: no immobility, general or whole-body immobility greater than 48 hours, limb (orthopedic) immobility, travel greater than 8 hours causing immobility within the previous 7 days, neurologic paralysis, or other immobility not listed above. Patients were followed for 45 days for outcome of venous thromboembolism, which required positive imaging results and clinical plan to treat. Odds ratios (ORs) were derived from logistic regression including 12 covariates. RESULTS From 7,940 patients enrolled, 545 of 7,940 (6.9%) were diagnosed with venous thromboembolism (354 pulmonary embolism, 72 deep venous thrombosis, 119 pulmonary embolism and deep venous thrombosis). Risk of venous thromboembolism varied, depending on immobility type: limb (OR=2.24; 95% confidence interval [CI] 1.40 to 3.60), general (OR=1.76; 95% CI 1.26 to 2.44), other (OR=1.97; 95% CI 1.25 to 3.09), neurologic (OR=2.23; 95% CI 1.01 to 4.92), and travel (OR=1.19; 95% CI 0.85 to 1.67). Other significant risk factors from multivariate analysis included age greater than 50 years (OR =1.5; 95% CI 1.25 to 1.82), unilateral leg swelling (OR=2.68; 95% CI 2.13 to 3.37), previous venous thromboembolism (OR=2.99; 95% CI 2.41 to 3.71), active malignancy (OR=2.23; 95% CI 1.69 to 2.95), and recent surgery (OR=2.12; 95% CI 1.61 to 2.81). CONCLUSION In a large cohort of symptomatic ED patients, risk of venous thromboembolism was substantially increased by presence of limb, whole-body, or neurologic immobility but not by travel greater than 8 hours. These data show the importance of clarifying the cause of immobility in risk assessment of venous thromboembolism.