Sex-related differences in D-dimer levels for venous thromboembolism screening.

BACKGROUND: D-dimer is generally considered positive above 0.5 mg/L irrespective of sex. However, women have been shown to be more likely to have a positive D-dimer after controlling for other factors. Thus, differences may exist between males and females for using D-dimer as a marker of venous thromboembolic (VTE) disease. We hypothesized that the accuracy of D-dimer tests may be enhanced by using appropriate cutoff values that reflect sex-related differences in D-dimer levels. METHODS: This research is a secondary analysis of a multicenter, international, prospective, observational study of adult (18+ years) patients suspected of VTE, with low-to-intermediate pretest probability based on Wells criteria ≤ 6 for pulmonary embolism (PE) and ≤ 2 for deep vein thrombosis (DVT). VTE diagnoses were based on computed tomography, ventilation perfusion scanning, or venous ultrasound. D-dimer levels were tested for statistical difference across groups stratified by sex and diagnosis. Multivariable regression was used to investigate sex as a predictor of diagnosis. Sex-specific optimal D-dimer thresholds for PE and DVT were calculated from receiver operating characteristic analyses. A Youden threshold (D-dimer level coinciding with the maximum of sensitivity plus specificity) and a cutoff corresponding to 95% sensitivity were calculated. Statistical difference for cutoffs was tested via 95% confidence intervals from 2,000 bootstrapped samples. RESULTS: We included 3,586 subjects for analysis, of whom 61% were female. Race demographics were 63% White, 27% Black/African American, and 6% Hispanic. In the suspected PE cohort, 6% were diagnosed with PE, while in the suspected DVT cohort, 11% were diagnosed with DVT. D-dimer levels were significantly higher in males than females for the PE-positive group and the DVT-negative group, but males had significantly lower D-dimer levels than females in the PE-negative group. Regression models showed male sex as a significant positive predictor of DVT diagnosis, controlling for D-dimer levels. The Youden thresholds for PE patients were 0.97 (95% CI = 0.64 to 1.79) mg/L and 1.45 (95% CI = 1.36 to 1.95) mg/L for females and males, respectively; 95% sensitivity cutoffs for this group were 0.64 (95% CI = 0.20 to 0.89) and 0.55 (95% CI = 0.29 to 1.61). For DVT, the Youden thresholds were 0.98 (95% CI = 0.84 to 1.56) mg/L for females and 1.25 (95% CI = 0.65 to 3.33) mg/L for males with 95% sensitivity cutoffs of 0.33 (95% CI = 0.2 to 0.61) and 0.32 (95% CI = 0.18 to 0.7), respectively. CONCLUSION: Differences in D-dimer levels between males and females are diagnosis specific; however, there was no significant difference in optimal cutoff values for excluding PE and DVT between the sexes.

Investigation of age-adjusted D-dimer using an uncommon assay.

BACKGROUND: Use of an age-adjusted D-dimer for the evaluation of acute pulmonary embolus (PE) has been prospectively validated in the literature and has become a practice recommendation from major medical societies. Most research on this subject involves the most common D-dimer assays reporting in Fibrinogen Equivalent Units (FEU) with a non-age-adjusted manufacturer-recommended cutoff of 500 ng/ml FEU. Limited research to date has evaluated age-adjustment in assays that report in D-Dimer Units (D-DU), which use a manufacturer-recommended cutoff of 230 ng/ml D-DU. Despite scant evidence, an age-adjusted formula using D-DU has been recently endorsed by the American College of Emergency Physicians (ACEP). This formula seems arbitrary in its derivation and unnecessarily deviates from existing thresholds, thus prompting the creation of our novel-age adjustment formula. The goal of this study was to retrospectively evaluate the test characteristics of our novel age-adjusted D-dimer formula using the D-DU assay in comparison to existing traditional and age-adjusted D-dimer thresholds for the evaluation of acute PE in the ED. METHODS: This was a retrospective chart review at an academic quaternary health system with three EDs and 195,000 combined annual ED visits. Only patients with D-dimer testing and CT PE protocol (CTPE) imaging were included. Admission and discharge diagnosis codes were used to identify acute PE. Outcome measures were sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of an unadjusted traditional threshold (230) compared with both novel and ACEP-endorsed age adjusted thresholds, (Age × 5) - 20 and Age × 5 if >50, respectively. Estimates with their exact 95% threshold were performed. RESULTS: 4846 adult patients were evaluated from January 2012 to July 2017. Group characteristics include a mean age of 52 and a frequency of acute PE diagnosis by CTPE of 8.25%. Traditional D-dimer cutoff demonstrated a sensitivity of 99.8% (95% CI 98.6-100), specificity of 16.7% (95% CI 15.6-17.8) and NPV of 99.9% (95% CI 99.3-100). Our novel age-adjusted D-dimer thresholds had a sensitivity of 97.0% (95% CI 94.8-98.4), specificity of 27.9% (95% CI 26.6-29.2) and NPV of 99.0% (95% CI 98.3-99.5) with the ACEP-endorsed formula demonstrating similar test characteristics. CONCLUSION: Use of an age-adjusted D-dimer on appropriately selected patients being evaluated for acute PE in the ED with a D-DU assay increases specificity while maintaining a high sensitivity and NPV. Both our novel formula and the ACEP-endorsed age-adjusted formula performed well, with our novel formula showing a trend towards improved testing characteristics.

International, multicenter evaluation of a new D-dimer assay for the exclusion of venous thromboembolism using standard and age-adjusted cut-offs.

INTRODUCTION: We sought to determine the test characteristics of an automated INNOVANCE D-dimer assay for the exclusion of pulmonary embolism (PE) and deep venous thrombosis (DVT) in emergency department (ED) patients using standard and age-adjusted cut-offs. METHODS: Cross-sectional, international, multicenter study of consecutive patients with suspected DVT or PE in 24 centers (18 USA, 6 Europe). Evaluated patients had low or intermediate Wells PE or DVT scores. For the standard cut-off, a D-dimer result <500 ng/ml was negative. For the age adjusted cut-off, we used the formula: Age (years) ∗ 10. The diagnostic standard was imaging demonstrating PE or DVT within 3 months. We calculated test characteristics using standard methods. We also explored modifications of the age adjustment multiplier. RESULTS: We included 3837 patients and excluded 251. The mean age of patients evaluated for PE (n = 1834) was 48 ±â€¯16 years, with 676 (37%) male, and 1081 (59%) white. The mean age of evaluated for DVT (n = 1752) was 53 ±â€¯16 years, with 710 (41%) male, and 1172 (67%) white. D-dimer test characteristics for PE were: sensitivity 98.0%, specificity 55.4%, negative predictive value (NPV) 99.8%, positive predictive value (PPV) 11.4%, and for DVT were: sensitivity 92.0%, specificity 44.8%, NPV 98.8%, PPV 10.3%. Age adjustment increased specificity (59.6% [PE], 51.1% [DVT]), but increasing the age-adjustment multiplier decreased sensitivity without increasing specificity. CONCLUSIONS: INNOVANCE D-dimer is highly sensitive and can exclude PE and DVT in ED patients with low- and intermediate- pre-test probability. Age-adjustment increases specificity, without increasing false negatives.

Correlation of Venous Blood Gas and Pulse Oximetry With Arterial Blood Gas in the Undifferentiated Critically Ill Patient.

RATIONALE: Blood gas analysis is often used to assess acid-base, ventilation, and oxygenation status in critically ill patients. Although arterial blood gas (ABG) analysis remains the gold standard, venous blood gas (VBG) analysis has been shown to correlate with ABG analysis and has been proposed as a safer less invasive alternative to ABG analysis. OBJECTIVE: The purpose of this study was to evaluate the correlation of VBG analysis plus pulse oximetry (SpO2) with ABG analysis. METHODS: We performed a prospective cohort study of patients in the emergency department (ED) and intensive care unit (ICU) at a single academic tertiary referral center. Patients were eligible for enrollment if the treating physician ordered an ABG. Statistical analysis of VBG, SpO2, and ABG data was done using paired t test, Pearson χ2, and Pearson correlation. MAIN RESULTS: There were 156 patients enrolled, and 129 patients completed the study. Of the patients completing the study, 53 (41.1%) were in the ED, 41 (31.8%) were in the medical ICU, and 35 (27.1%) were in the surgical ICU. The mean difference for pH between VBG and ABG was 0.03 (95% confidence interval: 0.03-0.04) with a Pearson correlation of 0.94. The mean difference for pCO2 between VBG and ABG was 4.8 mm Hg (95% confidence interval: 3.7-6.0 mm Hg) with a Pearson correlation of 0.93. The SpO2 correlated well with PaO2 (the partial pressure of oxygen in arterial blood) as predicted by the standard oxygen-hemoglobin dissociation curve. CONCLUSION: In this population of undifferentiated critically ill patients, pH and pCO2 on VBG analysis correlated with pH and pCO2 on ABG analysis. The SpO2 correlated well with pO2 on ABG analysis. The combination of VBG analysis plus SpO2 provided accurate information on acid-base, ventilation, and oxygenation status for undifferentiated critically ill patients in the ED and ICU.

Vomiting, diarrhea, constipation, and gastroenteritis.

Diseases that cause vomiting, diarrhea, constipation, and gastroenteritis are major problems for populations worldwide. Patients, particularly infants, elderly, and immunocompromised individuals, may present at any point in a wide spectrum of disease states, underscoring the need for the clinician to treat these ailments aggressively. Several promising new treatment modalities, from oral rehydration solutions to antiemetic therapies, have been introduced over the past decade. Future directions include the use of probiotic agents and better tolerated rehydration solutions. Gastrointestinal disease will continue to be a focus worldwide in the search for better ways to cure illnesses associated with vomiting and diarrhea.

The utility of handheld ultrasound in an austere medical setting in Guatemala after a natural disaster.

OBJECTIVE: To identify equipment needs, utility, clinical applications, and acuity of diagnoses made by hand-carried ultrasound (HCU) after a natural disaster. METHODS: An HCU with four probes (curved array, linear array, phased array, and endocavitary) was taken to the site of a natural disaster in Guatemala as part of the relief effort after mudslides killed approximately 1,000 people. Ultrasound (US) scans were classified by transducer type, anatomic region, presenting complaint, and therapeutic urgency of treatment. RESULTS: Ninety-nine patients received 137 US: 58 pelvic, 34 right upper quadrant, 23 renal, six other abdominal, five orthopedic, four cardiac, three pleura and lung, three soft tissue, and one focused assessment by sonography in trauma. Acuity of presenting illness: 23 percent <24 hours, 15 percent 1-14 days, 44 percent >14 days. Eighteen percent were performed in prenatal clinic. Results of US ruled in 12 percent with an emergent problem and excluded disease in 42 percent. In 14 percent, US diagnosed a problem needing flu in <2 weeks, and 32 percent with a problem needing long-term observation. Transducer utilization was general purpose curved array 88 percent, linear array 10 percent, endocavitary 8 percent, and phased array 4 percent. CONCLUSIONS: HCU has a range of applications in an austere medical setting after a natural disaster. Most can be dealt with using a single transducer.

Hemin induces an iron-dependent, oxidative injury to human neuron-like cells.

Hemin is released from hemoglobin after CNS hemorrhage and is present at high micromolar concentrations in intracranial hematomas. This highly reactive compound is potentially cytotoxic via a variety of oxidative and nonoxidative mechanisms. However, despite its clinical relevance, little is known of its effect on neuronal cells. In this study, we tested the hypotheses that hemin is toxic to human neurons at physiologically relevant concentrations and that its toxicity is iron dependent and oxidative. A homogeneous population of neuron-like cells was produced by sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor, using the protocol of Encinas et al. Hemin exposure for 24 hr resulted in cell death that progressively increased between 3 and 30 microM (EC(50) approximately 10 microM); protoporphyrin IX, the iron-free congener of hemin, was not toxic. Cell death commenced at 14 hr and was preceded by a marked increase in cellular reactive oxygen species (ROS). Most injury and ROS production were prevented by concomitant treatment with an equimolar concentration of the lipid-soluble iron chelator phenanthroline; the water-soluble chelator deferoxamine was also effective at concentrations of 0.1 mM or higher. Heme oxygenase-2 was constitutively expressed by these cells, and heme oxygenase-1 was induced by hemin. Heme oxygenase inhibition attenuated ROS generation and reduced injury by about one-third. Cell death was also prevented with the sulfhydryl reducing agents glutathione and mercaptoethanol. Nuclear morphology in the hours prior to cell lysis revealed a predominantly homogenous staining pattern; the percentage of fragmented nuclei was increased only at 4 hr and then accounted for only 1.45% +/- 0.25% of cells. The general caspase inhibitor zVAD-fmk had no effect on cell viability. These results suggest that hemin is toxic to human neuron-like cells at concentrations that are less than 3% of those observed in intracranial hematomas. In this model, its toxicity is iron dependent, oxidative, and predominantly necrotic.