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1.  Evaluation of Pulmonary Embolism in the Emergency Department and Consistency With a National Quality Measure 
Archives of internal medicine  2012;172(13):1028-1032.
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.
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. χ2 Test was used for bivariate analysis of categorical variables and multivariable logistic regression for the secondary analysis.
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).
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.
PMCID: PMC3775003  PMID: 22664742
2.  D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography 
Increasing the threshold to define a positive D-dimer could reduce unnecessary computed tomographic pulmonary angiography (CTPA) for suspected PE but might increase rates of missed PE and missed pneumonia, the most common nonthromboembolic diagnosis seen on CTPA.
Measure the effect of doubling the standard D-dimer threshold for “PE unlikely” Revised Geneva (RGS) or Wells’ scores on the exclusion rate, frequency and size of missed PE and missed pneumonia.
Patients evaluated for suspected PE with 64-channel CTPA were prospectively enrolled from EDs and inpatient units of four hospitals. Pretest probability data were collected in real time and the D-dimer was measured in a central laboratory. Criterion standard was CPTA interpretation by two independent radiologists combined with clinical outcome at 30 days.
Of 678 patients enrolled, 126 (19%) were PE+ and 93 (14%) had pneumonia. Use of either Wells≤4 or RGS≤6 produced similar results. For example, with RGS≤6 and standard threshold (<500 ng/mL), D-dimer was negative in 110/678 (16%), and 4/110 were PE+ (posterior probability 3.8%), and 9/110 (8.2%) had pneumonia. With RGS≤6 and a threshold <1000 ng/mL, D-dimer was negative in 208/678 (31%) and 11/208 (5.3%) were PE+, but 10/11 missed PEs were subsegmental, and none had concomitant DVT. Pneumonia was found in 12/208 (5.4%) with RGS≤6 and D-dimer<1000 ng/mL.
Doubling the threshold for a positive D-dimer with a PE unlikely pretest probability could reduce CTPA scanning with a slightly increased risk of missed isolated subsegmental PE, and no increase in rate of missed pneumonia.
PMCID: PMC3319270  PMID: 22284935
Fibrin fragment D; venous thromboembolism; medical decision making; tomography; spiral computed
3.  Factors Associated With Positive D-dimer Results in Patients Evaluated for Pulmonary Embolism 
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.
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.
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).
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.
PMCID: PMC3538031  PMID: 20624138
D-dimer; pulmonary embolism; venous thromboembolism; testing
4.  Simultaneous Acquisition of Phosphocreatine and Inorganic Phosphate Images for Pi:PCr Ratio Mapping Using a RARE Sequence with Chemically Selective Interleaving 
Magnetic resonance imaging  2011;29(8):1138-1144.
The ratio of inorganic phosphate (Pi) to phosphocreatine (PCr) is validated marker of mitochondrial function in human muscle. The MRI rapid acquisition with relaxation enhancement (RARE) pulse sequence can acquire phosphorus-31 (31P) images with higher spatial and temporal resolution than traditional spectroscopic methods, which can then be used to create Pi:PCr ratio maps of muscle regions. While the 31P RARE method produces images that reflect the content of the 31P metabolites, it has been limited to producing an image of only one chemical shift in a scan. This increases the scan time required to acquire images of multiple chemical shifts as well as the likelihood of generating inaccurate Pi:PCr maps due to gross motion. This work is a preliminary study to demonstrate the feasibility of acquiring Pi and PCr images in a single scan by interleaving Pi and PCr chemical shift acquisitions using a chemically selective RF excitation pulse. The chemical selectivity of the excitation pulse is evaluated and Pi:PCr maps generated using the interleaved Pi and PCr acquisition method with the subject at rest and during exercise are compared to those generated using separate Pi and PCr acquisition scans. A paired t-test indicated that the resulting Pi:PCr ratios for the exercised forearm muscle regions were not significantly different between the separate Pi and PCr acquisition method (3.18 ± 1.53) (mean ± standard deviation) and the interleaved acquisition method (3.41 ± 1.66). This work demonstrates the feasibility of creating Pi:PCr ratio maps in human muscle with Pi and PCr images acquired simultaneously by interleaving between the Pi and PCr resonances in a single scan.
PMCID: PMC3172363  PMID: 21641744
phosphorus metabolism; RARE MRI; chemical shift imaging; muscle metabolism
5.  The Feasibility of Measuring Phosphocreatine Recovery Kinetics in Muscle Using Single-Shot 31P RARE MRI Sequence 
Academic radiology  2011;18(7):917-923.
Rationale and Objectives
Heterogeneity of skeletal muscle structure, composition and perfusion results in spatial differences in oxidative function between muscles and muscle regions. The simultaneous measurement of the post-exercise phosphocreatine (PCr) recovery rate across all muscles of a human limb cross-section may provide new insights into normal physiology and disease states. The objective of this work was to assess the feasibility of acquiring PCr rapid acquisition with relaxation enhancement (RARE) images with sufficient temporal and spatial resolution to accurately measure PCr recovery kinetics in a cross-section of a human limb.
Materials and Methods
One normal subject performed a finger exercise until fatigued. At cessation of exercise surface coil localized pulse-and-acquire phosphorus-31 MR spectra (31P-MRS) of the forearm were acquired at 6 S intervals for 4 minutes. The exercise protocol was repeated 7 days later and axial PCr RARE images of the forearm were acquired following exercise with 5.6 cm3 voxels at 6 S intervals for 4 minutes.
The PCr recovery time constants for the PCr RARE and 31P-MRS measurements were 91.0 and 91.1 seconds, respectively based on a monoexponential fit. A Pearson correlation test showed that the PCr recovery data that resulted from the RARE PCr imaging were highly correlated with the data resulting from the 31P-MRS (r = 0.91, p<0.0001).
Data from selected regions of RARE PCr images acquired at 6 S intervals compare well to those acquired using surface coil 31P MR spectroscopy and can provide an accurate assessment of PCr recovery kinetics.
PMCID: PMC3115448  PMID: 21536463
MRI; phosphocreatine recovery kinetics; RARE MRI; muscle function; phosphorus MRI
6.  Evaluation of skeletal muscle during calf exercise by 31P MR spectroscopy in patients on statin medications 
Muscle & nerve  2011;43(1):76-81.
Muscle pain is a common side effect of statin medications, however, the cause is poorly understood.
We characterized phosphocreatine (PCr) exercise recovery kinetics in 10 patients with hypercholesterolemia before and after a 4 week regimen of statin therapy using 31P magnetic resonance spectroscopy (31P-MRS). 31P spectra were obtained before, during, and following exercise on a calf flexion pedal ergometer. Creatine kinase (CK) serum levels were drawn before and after statin therapy.
The mean metabolic recovery time constant in subjects increased from 28.1s (SE=6.5s) to 55.4s (SE=7.4s) following statin therapy. The unweighted mean of the pre-post recovery time difference was -27.3s (SE=12.4s); (p-value = 0.02). Pre- and post-therapy CK levels were not significantly different (p-value = 0.50).
Metabolic recovery time in the calf is prolonged in patients following statin use. This suggests that statins impair mitochondrial oxidative function, and 31P –MRS is a potential study model for statin-associated myopathy.
PMCID: PMC3332539  PMID: 21171098
Statin medications; MR spectroscopy; myopathy; phosphocreatine exercise recovery kinetics; mitochondrial disease
7.  Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects 
High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects.
This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated.
The AUC0-10 hr and Cmax values increased nonlinearly between100 mg and 1500 mg. The slope of the AUC0-10 hr vs dose, as well as the Cmax vs dose, plots are steepest at the lowest thiamine doses.
Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process.
Trial Registration NCT00981877
PMCID: PMC3293077  PMID: 22305197
8.  D-Dimer and Exhaled CO2/O2 to Detect Segmental Pulmonary Embolism in Moderate-Risk Patients 
Rationale: Pulmonary embolism (PE) decreases the exhaled end-tidal ratio of carbon dioxide to oxygen (etCO2/O2).
Objectives: To test if the etCO2/O2 can produce clinically important changes in the probability of segmental or larger PE on computerized tomography multidetector-row pulmonary angiography (MDCTPA) in a moderate-risk population with a positive D-dimer.
Methods: Emergency department and hospitalized patients with one or more predefined symptoms or signs, one or more risk factors for PE, and 64-slice MDCTPA enrolled from four hospitals. D-dimer greater than 499 ng/ml was test(+), and D-dimer less than 500 ng/ml was test(−). The median etCO2/O2 less than 0.28 from seven or more breaths was test(+) and etCO2/O2 greater than 0.45 was test(−). MDCTPA images were read by two independent radiologists and the criterion standard was the interpretation of acute PE by either reader. PE size was then graded.
Measurements and Main Results: We enrolled 495 patients, including 60 (12%) with segmental or larger, and 29 (6%) with subsegmental PE. A total of 367 (74%) patients were D-dimer(+), including all 60 with segmental or larger PE (posterior probability 16%). The combination of D-dimer(+) and etCO2/O2(+) increased the posterior probability of segmental or larger PE to 28% (95% confidence interval [CI] for difference of 12%, 3.0–22%). The combination of D-dimer(+) and etCO2/O2(−) was observed in 40 patients (8%; 95% CI, 6–11%), and none (0/40; 95% CI, 0–9%) had segmental or larger PE on MDCTPA. No strategy changed the prevalence of subsegmental PE.
Conclusions: In moderate-risk patients with a positive D-dimer, the et etCO2/O2 less than 0.28 significantly increases the probability of segmental or larger PE and the etCO2/O2 greater than 0.45 predicts the absence of segmental or larger PE on MDCTPA.
Clinical trial registered with (NCT 00368836).
PMCID: PMC2937237  PMID: 20448094
fibrin fragment D; venous thromboembolism; medical decision making; capnography; tomography, spiral computed
9.  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, multi-center study 
Annals of emergency medicine  2010;55(4):307-315.e1.
Study Objective
Prediction rules for pulmonary embolism (PE) employ variables explicitly shown to estimate the probability of PE. However, clinicians often use variables that have not been similarly validated, yet are implicitly believed to modify probability of PE. The objective of this study was to measure the predictive value of 13 implicit variables.
Patients were enrolled in a prospective cohort study from 12 centers in the United States; all had an objective test for PE (D-dimer, CT angiography, or V/Q 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 VTE (venous thromboembolism: PE 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.
7,940 patients (7.2% VTE+) were enrolled. Mean age was 49±17 years and 67% were female. Eight of 13 implicit variables were significantly associated with VTE; those with an adjusted OR >1.5 included non-cancer related thrombophilia (1.99), pleuritic chest pain (1.53), and family history of VTE (1.51). Implicit variables that predicted no VTE outcome included: substernal chest pain, female gender, and smoking. Nine of 12 explicit variables predicted a positive outcome of VTE, including unilateral leg swelling, recent surgery, estrogen, hypoxemia and active malignancy.
In symptomatic outpatients being considered for possible PE, non-cancer related thrombophilia, pleuritic chest pain, and family history of VTE increase probability of PE or DVT. Other variables that are part of existing pretest probability systems were validated as important predictors in this diverse sample of US Emergency department patients.
PMCID: PMC2847003  PMID: 20045580
Prediction; decision rules; logistic regression; D-dimer; pulmonary embolism
10.  Coronary Artery Bypass Graft (CABG) surgery depletes plasma thiamine levels 
Thiamine is an essential component of cellular metabolism, and lack of this vitamin results in a potentially life-threatening biochemical lesion. The stress of surgery and critical disease depletes electrolytes, minerals, and essential biochemical substrates. We hypothesized that critical illness (represented by major surgery) will result in decreased thiamine levels over time.
We performed a prospective, observational study of serial thiamine levels of 15 patients who underwent non-emergent coronary artery bypass graft (CABG) surgery. The primary endpoint was change in thiamine levels from pre- to immediately post-surgery. Secondary endpoints included change in thiamine levels between pre- surgery and 6 and 24 hour time-points.
Of the 15 study patients, one did not have a plasma thiamine measurement at time zero because of lab error and could not be accounted for in paired comparisons over time. Plasma thiamine levels decreased significantly from the pre to post-CABG period (p = 0.0004). In addition, there was a statistically significant decrease in thiamine levels from pre-surgery to 24 hours (P = 0.003).
Our data suggest that major surgery (as a surrogate for the stress of critical illness) depletes thiamine levels; further study is needed to determine whether routine replacement of thiamine in the critically ill is warranted.
PMCID: PMC2874825  PMID: 20005469
Thiamine deficiency; critical illness; coronary artery bypass graft surgery
11.  Acute decompensated heart failure 
PMCID: PMC1913128  PMID: 17638957
12.  A report of dangerously high carbon monoxide levels within the passenger compartment of a snow-obstructed vehicle 
We sought to determine how quickly carbon monoxide would accumulate in the passenger compartment of a snow-obstructed vehicle.
A 1992 sedan was buried in snow to the level of the undercarriage, the ignition was then engaged and carbon monoxide levels recorded at 2.5-minute intervals. The primary outcome was the time at which a lethal carbon monoxide level was detected. Six trials were conducted: windows closed; windows open one inch; windows open 6 inches; windows closed and tailpipe swept clear of snow; windows closed and one cubic foot of snow removed around tailpipe; windows closed and tailpipe completely cleared of snow to ground level in a path 12 inches wide.
Lethal levels of carbon monoxide occurred within 2.5 minutes in the vehicle when the windows were closed, within 5 minutes when the widows were opened one inch, and within 7.5 minutes when the widows were opened six inches. Dangerously high levels of carbon monoxide were detected within the vehicle when the tailpipe had been swept clear of snow and when a one cubic foot area had been cleared around the tailpipe. When the tailpipe was completely unobstructed the carbon monoxide level was zero.
Lethal levels of carbon monoxide occurred within minutes in this snow-obstructed vehicle.
PMCID: PMC526190  PMID: 15473913
13.  Beckman Access versus the Bayer ACS:180 and the Abbott AxSYM cardiac Troponin-I real-time immunoassays: an observational prospective study 
Reliability of cardiac troponin-I assays under real-time conditions has not been previously well studied. Most large published cTnI trials have utilized protocols which required the freezing of serum (or plasma) for delayed batch cTnI analysis. We sought to correlate the presence of the acute ischemic coronary syndrome (AICS) to troponin-I values obtained in real-time by three random-mode analyzer immunoassay systems: the Beckman ACCESS (BA), the Bayer ACS:180 (CC) and the Abbott AxSYM (AX).
This was an observational prospective study at a university tertiary referral center. Serum from a convenience sampling of telemetry patients was analyzed in real-time for troponin-I by either the BA-CC (Arm-1) or BA-AX (Arm-2) assay pairs. Presence of the AICS was determined retrospectively and then correlated with troponin-I results.
100 patients were enrolled in Arm-1 (38 with AICS) and 94 in Arm-2 (48 with AICS). The BA system produced 51% false positives in Arm-1, 44% in Arm-2, with negative predictive values of 92% and 100% respectively. In Arm-1, the BA and the CC assays had sensitivities of 97% and 63% and specificities of 18% and 87%. In Arm-2, the BA and the AX assays had sensitivities of 100% and 83% and specificities of 11% and 78%.
In real-time analysis, the performance of the AxSYM and ACS:180 assay systems produced more accurate troponin-I results than the ACCESS system.
PMCID: PMC487900  PMID: 15248900

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