Karl G. Hock

Diagnostic Utility of Plasma Procalcitonin for Nosocomial Pneumonia in the Intensive Care Unit Setting

BACKGROUND: Nosocomial pneumonia is a difficult diagnosis to establish in the intensive care unit setting, due to the non-specific nature of the clinical and radiographic findings. Procalcitonin is a circulating biomarker that may become elevated in the presence of bacterial infection. METHODS: We conducted a prospective single-center cohort study at Barnes-Jewish Hospital, a 1,200-bed urban teaching hospital in St Louis, Missouri. In medical and surgical intensive care unit patients with suspected nosocomial pneumonia we measured plasma procalcitonin with an enzyme-linked fluorescent assay. RESULTS: We evaluated 104 consecutive patients with suspected nosocomial pneumonia, 67 (64%) of whom met our predefined clinical and microbiologic criteria for definite nosocomial pneumonia. Though the mean procalcitonin concentration was greater in the 67 patients with definite nosocomial pneumonia (18.3 ± 99.1 ng/mL, median 0.8 ng/mL, 5th percentile 0.0 ng/mL, 95th percentile 43.1 ng/mL) than in the 12 patients with definite absence of nosocomial pneumonia (1.7 ± 2.0 ng/mL, median 1.0 ng/mL, 5th percentile 0.0 ng/mL, 95th percentile 6.7 ng/mL), this difference was not statistically significant (P = .66). A procalcitonin cutoff value of > 1 ng/mL yielded a diagnostic sensitivity of 50% and a specificity of 49% for definite nosocomial pneumonia. Receiver operating curve and multivariate logistic regression analyses demonstrated that procalcitonin is inferior to clinical variables for diagnosing nosocomial pneumonia. However, compared to patients with an initial procalcitonin > 1 ng/mL, those with lower procalcitonin had fewer total antibiotic days (13.0 ± 10.3 d vs 19.7 ± 12.0 d, P < .001) and fewer antibiotic days for treatment of nosocomial pneumonia (10.0 ± 5.9 d vs 14.7 ± 7.4 d, P < .001). CONCLUSIONS: Plasma procalcitonin has minimal diagnostic value for nosocomial pneumonia.

Short- and Long-term Biologic Variability of Galectin-3 and Other Cardiac Biomarkers in Patients with Stable Heart Failure and Healthy Adults

BACKGROUND Galectin-3 (Gal-3) has been suggested as a prognostic biomarker in heart failure (HF) patients that may better reflect disease progression than traditional markers, including B-type natriuretic peptide (BNP) and cardiac troponins. To fully establish the utility of any biomarker in HF, its biologic variability must be characterized. METHODS To assess biologic variability, 59 patients were prospectively recruited, including 23 male and 16 female patients with stable HF and 10 male and 10 female healthy individuals. Gal-3, BNP, and high-sensitivity cardiac troponin I (hs-cTnI) were assayed at 5 time points within a 3-week period to assess short-term biologic variability. Long-term (3-month) biologic variability was assessed with samples collected at enrollment and after 4, 8, and 12 weeks. RESULTS Among healthy individuals, mean short-term biologic variability, expressed as intraindividual CV (CVI), was 4.5% for Gal-3, 29.0% for BNP, and 14.5% for hs-cTnI; long-term biologic variability was 5.5% for Gal-3, 34.7% for BNP, and 14.7% for hs-cTnI. In stable HF patients, mean short-term biologic variability was 7.1% for Gal-3, 22.5% for BNP, and 8.5% for hs-cTnI, and mean long-term biologic variability was 7.7% for Gal-3, 27.6% for BNP, and 9.6% for hs-cTnI. CONCLUSIONS The finding that Gal-3 has minimal intraindividual biological variability adds to its potential as a useful biomarker in HF patients.

Performance characteristics of a no-pretreatment, random access sirolimus assay for the Dimension RxL clinical chemistry system.

OBJECTIVES Current therapeutic drug monitoring methods for sirolimus require a manual pre-treatment step and batch analysis. We describe and validate a no-pretreatment, random access sirolimus assay for the Dimension RxL clinical chemistry system from Siemens Healthcare Diagnostics Inc. DESIGN AND METHODS Whole blood samples from renal transplant patients prescribed sirolimus were analyzed by the LC-MS/MS reference method, Abbott IMx and Dimension RxL methods in accordance with CLSI recommendations. RESULTS The Dimension sirolimus assay had a functional sensitivity of 2.0 ng/mL and repeatability and within-laboratory imprecision less than 12.6% at 3 ng/mL and less than 5% at 11-12 ng/mL. Least squares linear regression demonstrated the following relationships: RxL=1.20(LC-MS/MS) - 0.70, r=0.95 and RxL=1.33(IMx) - 0.75, r=0.96. CONCLUSIONS The Dimension sirolimus assay correlates well with the LC-MS/MS reference and IMx immunoassay methods and has the advantage of random access analysis without a manual pre-treatment step.

Hitachi Hemolytic Index correlates with HBOC-201 concentrations: impact on suppression of analyte results.

OBJECTIVES To determine the feasibility of laboratories to use an instruments Hemolytic Index (HI) to determine if a test result would be accurate in the presence of hemoglobin-based oxygen carrier HBOC-201. DESIGN AND METHODS HI values from the Roche Hitachi Modular P800 for samples containing HBOC-201 were determined. HI limits for 24 tests determined by addition of RBC lysate hemoglobin to serum and the instrument manufacturers HI limits were compared to HI limits for reporting the same tests determined by adding HBOC-201 to plasma. RESULTS There is a linear relationship (R(2)=0.99) between the HI value on the Modular P800 and HBOC-201 concentrations. Twenty-one of 24 HI limits for reporting results as determined by the manufacturer or adding RBC lysate to serum were more conservative or equal to the limit determined by HBOC-201 interference testing. HBOC-201 interference testing was more conservative for albumin, creatinine, and uric acid. CONCLUSION For most analytes, the Modular P800 HI provides an accurate, conservative and automated method to determine whether laboratory results should be reported or suppressed when samples contain HBOC-201.

Establishing reference intervals for hCG in postmenopausal women.

BACKGROUND Plasma concentrations of human chorionic gonadotropin (hCG) have been shown to increase with age due to pituitary secretion. We previously recommended that an hCG cutoff of 14.0IU/L be used for women ≥55years of age. However, it remains unknown whether concentrations >14.0IU/L can be expected in women with advanced age. Our objectives were to establish plasma hCG reference intervals and correlate follicle stimulating hormone (FSH) and hCG concentrations in postmenopausal females ≥55years. METHODS Residual plasma samples from 798 women ≥55years were utilized with 303, 269, and 226 samples belonging to the age groups 55-69, 70-84, and ≥85years, respectively. FSH and hCG were measured using the Abbott ARCHITECT. All positive hCG samples (hCG ≥5IU/L) were analyzed for potential heterophile antibody interference and 3 were excluded. Electronic medical records were reviewed and patients with malignancy were excluded. RESULTS 8% (56/666) of women age≥55years had plasma hCG ≥5IU/L. There were 19, 16, and 21 patients with hCG ≥5IU/L in the age groups 55-69, 70-84, and ≥85years, respectively. The highest hCG concentrations observed in each age group were: 55-69years maximum=11.7IU/L and 97.5th percentile=9.6IU/L; 70-84years maximum=18.09IU/L, 97.5th percentile=6.2IU/L; ≥85years maximum=11.1IU/L and 97.5th percentile=10.0IU/L, and the overall 97.5th percentile=8.5IU/L for all women ≥55years of age. Neither hCG nor FSH concentrations continued to increase with age in women ≥55years. CONCLUSIONS The prevalence of positive hCG in women ≥55years is 8%. This study confirms our previously recommended cutoff of 14IU/L for women ≥55years of age. In women ≥55years of age, FSH concentrations do not predict hCG concentrations.

Can tapentadol cause a false-positive urine drug screen result for amphetamine?

Tapentadol (Nucynta ® Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ.), is a newer, synthetic analgesic approved in the US in 2008 (immediate-release) and 2011 (extended-release) for acute or chronic management of moderate to severe pain. Tapentadol acts as both a mu opioid receptor agonist and norepinephrine reuptake inhibitor.1, 2 Activity at the alpha-2 adrenoreceptor may, directly or indirectly, contribute to its analgesic effect.3 In comparison to oxycodone, tapentadol has similar analgesia with fewer side effects, delayed tolerance, and reduced withdrawal symptoms.4, 5 Tapentadol (Fig. 1) is structurally similar to amphetamine (Fig. 2). Based upon our prior study showing frequent false positive amphetamine screens with other similar drugs such as bupropion,6 we sought to determine whether therapeutic use of tapentadol would be associated with false positive immunoassay amphetamine urine drug screens. Fig. 1 Structure of tapentadol. (Source: http://en.wikipedia.org). Fig. 2 Generic structure of amphetamine. (Source: http://en.wikipedia.org). We recruited patients from a pain management clinic and a rheumatology clinic into a prospective, IRB-approved study. We screened computerized clinic records to identify all patients with scheduled appointments in June through August 2011 and with recorded prescriptions for tapentadol. We met eligible patients on their scheduled appointment days and explained the purpose of the study. We excluded patients who were taking prescription amphetamines or bupropion, who admitted illicit amphetamine use, or who had not taken tapentadol within the 3 days before screening. Screened patients were explicitly allowed to opt out without stating a reason. Enrolled patients provided a spontaneously voided urine specimen on the day of their office visit, which we tested using the Siemens Syva EMIT II ™ immunoassay (Siemens Healthcare Diagnostics; Deerfield, IL). All positive immunoassays would then be confirmed by thin-layer chromatography. We recorded each patients prescribed dose and asked patients to report the number of doses taken on the study day and the two preceding days. We screened 21 patients taking tapentadol. We excluded 10 patients (3 had not taken the drug recently, 2 had excluding medications, 2 missed their appointments, 2 declined, 1 researcher unavailable). We enrolled 11 patients (8 women, 3 men) with ages ranging from 31 to 86 years (mean 49.5, median 50). Daily dose ranged from 50 mg/day to the maximum labeled dose of 600 mg/day (mean 268 mg/day, median 200 mg/day). All patients were taking the immediate-release formulation only. All urine specimens produced a negative immunoassay result for amphetamine in all 11 patients. We relied upon patient self-report for the quantity of tapentadol used in the days before study enrollment, and we did not confirm the presence of tapentadol metabolite in the urine. However, all the screened patients were aware of the purpose of the study and received no compensation for their participation, so we believe their self-reported recent doses to be accurate. Tapentadol shares structural similarities with both amphetamine and methadone. Although we found no amphetamine cross-reaction with the immunoassay, another recent study has demonstrated cross-reactivity with a similar immunoassay for methadone.7 We conclude that therapeutic use of tapentadol up to the maximum recommended dose of 600 mg/day does not produce a false positive urine amphetamine screen.

Does therapeutic use of tapentadol cause false-positive urine screens for methadone or opiates?

Aliquots from all specimens underwent quantitation of tapentadol and N-desmethyltapentadol by Mayo Medical Laboratories. After the addition of ammonium acetate buffer and beta-glucuronidase to liberate glucuronide-conjugated tapentadol and N-desmethyltapentadol, each sample underwent the LC–MS/MS method described by Coulter et al.4 For each analyte, the lower limit of quantitation is 50 ng/mL and the upper reporting limit is 50,000 ng/mL. Table 1 shows the patients’ self-reported doses of tapentadol, EMIT results for methadone and opiates, confirmatory test results, active prescriptions, and quantitation of tapentadol and N-desmethyltapentadol. Our results differ from those of Collins et al., who found frequent false-positive urine screens for methadone among patients taking tapentadol.3 The Collins study used the DRI Methadone EIA,5 a cloned enzyme donor immunoassay, which may have different performance characteristics from the Syva EMIT II immunoassay. They also used a lower threshold for methadone concentration of 130 ng/mL instead of the standard cutoff of 300 ng/mL. This lower threshold may increase the reported number of false-positive results. Clinical Toxicology (2015), 53, 493–494 Copyright