Improvement of Emergency Department Chest Pain Evaluation Using Hs-cTnT and a Risk Stratification Pathway.

BACKGROUND: Chest pain is among the most common reasons for presentation to the emergency department (ED) worldwide. Additional studies on most cost-effective ways of differentiating serious vs. benign causes of chest pain are needed. OBJECTIVES: Our study aimed to evaluate the effectiveness of a novel risk stratification pathway utilizing 5th generation high-sensitivity cardiac troponin T assay (Hs-cTnT) and HEART score (History, Electrocardiogram, Age, Risk factors, Troponin) in assessing nontraumatic chest pain patients in reducing ED resource utilization. METHODS: A retrospective chart review was performed 6 months prior to and after the implementation of a novel risk stratification pathway that combined hs-cTnT with HEART score to guide evaluation of adult patients presenting with nontraumatic chest pain at a large academic quaternary care ED. Primary outcome was ED length of stay (LOS); secondary outcomes included cardiology consult rates, admission rates, number of ED boarders, and number of eloped patients. RESULTS: A total of 1707 patients and 1529 patients were included pre- and postimplementation, respectively. Median overall ED LOS decreased from 317 to 286 min, an absolute reduction of 31 min (95% confidence interval 22-41 min), after pathway implementation (p < 0.001). Furthermore, cardiology consult rate decreased from 26.9% to 16.0% (p < 0.0001), rate of admission decreased from 30.1% to 22.7% (p < 0.0001), and number of ED boarders as a proportion of all nontraumatic chest pain patients decreased from 25.13% preimplementation to 18.63% postimplementation (p < 0.0001). CONCLUSIONS: Implementation of our novel chest pain pathway improved numerous ED throughput metrics in the evaluation of nontraumatic chest pain patients.

Cannabis positivity rates in 17 emergency departments across the United States with varying degrees of marijuana legalization.

BACKGROUND: Many states in the United States have progressed towards legalization of marijuana including decriminalization, medicinal and/or recreational use. We studied the impact of legalization on cannabis-related emergency department visits in states with varying degrees of legalization. METHODS: Seventeen healthcare institutions in fifteen states (California, Colorado, Connecticut, Florida, Iowa, Kentucky, Maryland, Massachusetts, Missouri, New Hampshire, Oregon, South Carolina, Tennessee, Texas, Washington) participated. Cannabinoid immunoassay results and cannabis-related International Classification of Diseases (ninth and tenth versions) codes were obtained for emergency department visits over a 3- to 8-year period during various stages of legalization: no state laws, decriminalized, medical approval before dispensaries, medical dispensaries available, recreational approval before dispensaries and recreational dispensaries available. Trends and monthly rates of cannabinoid immunoassay and cannabis-related International Classification of Diseases code positivity were determined during these legalization periods. RESULTS: For most states, there was a significant increase in both cannabinoid immunoassay and International Classification of Diseases code positivity as legalization progressed; however, positivity rates differed. The availability of dispensaries may impact positivity in states with medical and/or recreational approval. In most states with no laws, there was a significant but smaller increase in cannabinoid immunoassay positivity rates. CONCLUSIONS: States may experience an increase in cannabis-related emergency department visits with progression toward marijuana legalization. The differences between states, including those in which no impact was seen, are likely multifactorial and include cultural norms, attitudes of local law enforcement, differing patient populations, legalization in surrounding states, availability of dispensaries, various ordering protocols in the emergency department, and the prevalence of non-regulated cannabis products.

AACC Guidance Document on the Clinical Use of Procalcitonin.

BACKGROUND: Procalcitonin (PCT), a peptide precursor of the hormone calcitonin, is a biomarker whose serum concentrations are elevated in response to systemic inflammation caused by bacterial infection and sepsis. Clinical adoption of PCT in the United States has only recently gained traction with an increasing number of Food and Drug Administration-approved assays and expanded indications for use. There is interest in the use of PCT as an outcomes predictor as well as an antibiotic stewardship tool. However, PCT has limitations in specificity, and conclusions surrounding its utility have been mixed. Further, there is a lack of consensus regarding appropriate timing of measurements and interpretation of results. There is also a lack of method harmonization for PCT assays, and questions remain regarding whether the same clinical decision points may be used across different methods. CONTENT: This guidance document aims to address key questions related to the use of PCT to manage adult, pediatric, and neonatal patients with suspected sepsis and/or bacterial infections, particularly respiratory infections. The document explores the evidence for PCT utility for antimicrobial therapy decisions and outcomes prediction. Additionally, the document discusses analytical and preanalytical considerations for PCT analysis and confounding factors that may affect the interpretation of PCT results. SUMMARY: While PCT has been studied widely in various clinical settings, there is considerable variability in study designs and study populations. Evidence to support the use of PCT to guide antibiotic cessation is compelling in the critically ill and in some lower respiratory tract infections but is lacking in other clinical scenarios, and evidence is also limited in the pediatric and neonatal populations. Interpretation of PCT results requires guidance from multidisciplinary care teams of clinicians, pharmacists, and clinical laboratorians.

Current State of Pediatric Reference Intervals and the Importance of Correctly Describing the Biochemistry of Child Development: A Review.

Importance: Appropriately established pediatric reference intervals are critical to the clinical decision-making process and should reflect the physiologic changes that occur during healthy child development. Reference intervals used in pediatric care today remain highly inconsistent across a broad range of common clinical biomarkers. Observations: This narrative review assesses biomarker-specific pediatric reference intervals and their clinical utility with respect to the underlying biological changes occurring during development. Pediatric reference intervals from PubMed-indexed articles published from January 2015 to April 2021, commercial laboratory websites, study cohorts, and pediatric reference interval books were all examined. Although large numbers of pediatric reference intervals are published for some biomarkers, very few are used by clinical and commercial laboratories. The patterns, extent, and timing of biomarker changes are highly variable, particularly during developmental stages with rapid physiologic changes. However, many pediatric reference intervals do not capture these changes and thus do not accurately reflect the underlying biochemistry of development, resulting in significant inconsistencies between reference intervals. Conclusions and Relevance: There is a need to correctly describe the biochemistry of child development as well as to identify strategies to develop accurate and consistent pediatric reference intervals for improved pediatric care.

AACC Guidance Document on Laboratory Testing for the Assessment of Preterm Delivery.

Identifying women with preterm labor who will go on to deliver prematurely is crucial to improving outcomes for mother and baby and for saving healthcare resources. Even among those with symptoms, the number of women who deliver preterm is low, and thus the low positive predictive value (PPV) and high negative predictive value (NPV) associated with available biomarkers does not substantially reduce the uncertainty of the clinical diagnosis. While there is some promise in the use of fetal fibronectin (fFN), interleukin 6 (IL-6), or placental alpha microglobulin 1 (PAMG-1) for predicting preterm birth (PTB), their use is unlikely to provide considerable clinical value in populations with a low prevalence. To provide real clinical benefit, a biomarker must demonstrate a high PPV to allow identification of the minority of symptomatic women who will deliver prematurely. As none of the currently available biomarkers exhibit this performance characteristic, we do not recommend their routine clinical use in populations with a pre-test probability of PTB of <5%. Limiting biomarker testing to only high-risk women identified on the basis of cervical length or other characteristics will increase the pre-testprobability in the tested population, thereby improving PPV. PAMG-1 is associated with a higher PPV than fFN and may show clinical utility in populations with a higher pre-test probability, but further work is required to conclusively demonstrate improved outcomes in this patient group.

Procalcitonin: Usefulness in Acute Care Surgery and Trauma.

BACKGROUND: Procalcitonin (PCT) is a serum biomarker currently suggested by the Surviving Sepsis Campaign to aid in determination of the appropriate duration of therapy in sepsis patients. We review the use of procalcitonin in patients after trauma or acute care surgery. METHOD: A MEDLINE search via PubMed was performed using the combination of "procalcitonin" and "humans" and "injuries, trauma," "wounds and injuries," or "wounds." Studies of burn patients, children, other biomarkers, and non-acute care surgery were excluded. RESULTS: Procalcitonin may be useful in identifying infection in trauma and post-operative acute care surgery. However, heterogenity exists among patients, and surgery and trauma alone elevate PCT even in the absence of infection. CONCLUSIONS: Although trends in PCT concentrations may offer insight, no standard approach can be recommended currently.

Procalcitonin as an Early Marker of the Need for Invasive Respiratory or Vasopressor Support in Adults With Community-Acquired Pneumonia.

BACKGROUND: Predicting the need for intensive care among adults with community-acquired pneumonia (CAP) remains challenging. METHODS: Using a multicenter prospective cohort study of adults hospitalized with CAP, we evaluated the association of serum procalcitonin (PCT) concentration at hospital presentation with the need for invasive respiratory or vasopressor support (IRVS), or both, within 72 h. Logistic regression was used to model this association, with results reported as the estimated risk of IRVS for a given PCT concentration. We also assessed whether the addition of PCT changed the performance of established pneumonia severity scores, including the pneumonia severity index and the American Thoracic Society minor criteria, for prediction of IRVS. RESULTS: Of 1,770 enrolled patients, 115 required IRVS (6.5%). Using the logistic regression model, PCT concentration had a strong association with IRVS risk. Undetectable PCT (< 0.05 ng/mL) was associated with a 4% (95% CI, 3.1%-5.1%) risk of IRVS. For concentrations < 10 ng/mL, PCT had an approximate linear association with IRVS risk: for each 1 ng/mL increase in PCT, there was a 1% to 2% absolute increase in the risk of IRVS. With a PCT concentration of 10 ng/mL, the risk of IRVS was 22.4% (95% CI, 16.3%-30.1%) and remained relatively constant for all concentrations > 10 ng/mL. When added to each pneumonia severity score, PCT contributed significant additional risk information for the prediction of IRVS. CONCLUSIONS: Serum PCT concentration was strongly associated with the risk of requiring IRVS among adults hospitalized with CAP and is potentially useful for guiding decisions about ICU admission.

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery.

AIMS: One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. METHODS: We measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. RESULTS: Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h(-1) (2.2-9.2 l h(-1) ), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. CONCLUSIONS: We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

Utilization of assay performance characteristics to estimate hemoglobin A1c result reliability.

BACKGROUND: Allowable total error (TE(a)) goals for hemoglobin (Hb) A(1c) require minimal assay imprecision and bias and implementation of a robust QC monitoring program. Here, we compare the combined influence on the risk of reporting unreliable results of TE(a) goals, a routine QC practice, and assay performance characteristics of 6 Hb A(1c) instruments across 4 academic medical centers. METHODS: The CLSI protocols EP-5 and EP-9 were applied to investigate Hb A(1c) result imprecision and bias on the Variant II Turbo and Variant II (Bio-Rad), G8 (Tosoh), Capillarys 2 Flex Piercing (Sebia), COBAS Integra 800 (Roche), and DCA Vantage (Siemens). Patient-weighted σ values and the risk of reporting unreliable Hb A(1c) results were determined for each assay at TE(a) specifications of 5%, 6%, and 7%. RESULTS: A large range of patient-weighted σ values spanning 0.5 orders of magnitude at a 6% TE(a) was observed. Although imprecision for all instruments was <3%, bias impacted the majority of the σ changes observed. Estimates for reporting unreliable results varied almost 500-fold based on analytical performance alone. CONCLUSIONS: Considerable differences in the probability of reporting unreliable Hb A(1c) results between different NGSP (formerly the National Glycohemoglobin Standardization Program)-certified platforms were observed. At a 6% TE(a), our study indicates all but the Capillarys 2 Flex Piercing requires that the maximum affordable QC be run. Risk estimates for individual laboratories' Hb A(1c) methods can be used to assess QC practices and residual risk of an unreliable Hb A(1c) result.

Hypercalcemia secondary to gastrointestinal stromal tumors: parathyroid hormone-related protein independent mechanism?

OBJECTIVE: Hypercalcemia is a common paraneoplastic manifestation of many malignancies like breast, ovarian, and squamous-cell cancers of head and neck; however, there have been only a few case reports of hypercalcemia associated with gastrointestinal stromal tumors (GISTs). We report a case of GIST presenting with hypercalcemia without any osseous metastasis and provide a literature review regarding the mechanisms of hypercalcemia and therapeutic strategies. METHODS: We present a report of case and a review of the relevant literature. RESULTS: A 52-year-old woman with history of localized breast cancer in remission and a pelvic 13 × 12 cm GIST with peritoneal, liver, and lung metastases presented with hypercalcemia of 14.3 mg/dL (8.5-10.5 mg/dL). Parathyroid hormone-related protein (PTHrP) was undetectable, intact parathyroid hormone (PTH) was appropriately low at 1 pg/mL (10-65 pg/mL), and 1,25 dihydroxy vitamin D (1,25 OH2 vit D) was elevated at 131 pg/mL (18-78 pg/mL) with normal renal function. Calcium responded transiently to tyrosine kinase inhibitor therapy and bisphosphonates but within a year, she expired due to tumor progression. CONCLUSION: GIST is a rare cause of hypercalcemia. In addition to PTHrP expression, direct tumor production of 1,25(OH)2 vit D or 1-α hydroxylase enzyme resulting in activation of 25-hydroxy vitamin D may be an alternative mechanism in GIST-related hypercalcemia. Therapy with tyrosine kinase inhibitors and bisphosphonates is recommended, though prognosis is poor. Further investigations are needed to characterize the etiology and management of hypercalcemia in these patients.

Progestogens for preterm birth prevention: a systematic review and meta-analysis by drug route.

PURPOSE: Progestogen has been investigated as a preventive intervention among women with increased preterm birth risk. Our objective was to systematically review the effectiveness of intramuscular (IM), vaginal, and oral progestogens for preterm birth and neonatal death prevention. METHODS: We included articles published from January 1966 to January 2013 and found 27 randomized trials with data for Bayesian meta-analysis. RESULTS: Across all studies, only vaginal and oral routes were effective at reducing preterm births (IM risk ratio [RR] 0.95, 95 % Bayesian credible interval [BCI]: 0.88-1.03; vaginal RR 0.87, 95 % BCI: 0.80-0.94; oral RR 0.64, 95 % BCI: 0.49-0.85). However, when analyses were limited to only single births all routes were effective at reducing preterm birth (IM RR 0.77, 95 % BCI: 0.69-0.87; vaginal RR 0.80, 95 % BCI: 0.69-0.91; oral RR 0.66, 95 % BCI: 0.47-0.84). Only IM progestogen was effective at reducing neonatal deaths (IM RR 0.78, 95 % BCI: 0.56-0.99; vaginal RR 0.75, 95 % BCI: 0.45-1.09; oral RR 0.72, 95 % BCI: 0.09-1.74). Vaginal progestogen was effective in reducing neonatal deaths when limited to singletons births. CONCLUSIONS: All progestogen routes reduce preterm births but not neonatal deaths. Future studies are needed that directly compare progestogen delivery routes.

Analytical and clinical validation of the Immulite 1000 hCG assay for quantitative analysis in urine.

BACKGROUND: The Siemens Immulite hCG assay detects all major hCG variants in serum. Currently, this assay is only FDA approved for qualitative measurement of hCG in urine. METHODS: Complete validation of the hCG assay in urine was performed on the Siemens Immulite 1000 immunoassay platform. Reference intervals were established for females <55 y, females ≥55 y, and males 20-70 y. RESULTS: The limit of quantitation was 2.0 IU/l. The Immulite hCG assay was precise for measuring hCG in urine from pregnant patients with intra- and inter-assay imprecision of <11% CV. The assay was linear over a dynamic range of 2-2600 IU/l and 2-3500 IU/l for hCG and hCGß respectively. The assay was non-linear for hCGßcf. No hook effect was observed at concentrations up to 1,200,000 pmol/l, for hCGß or hCGßcf. The reference intervals were <2.0 IU/l for males, <2.2I U/l for females <55 y, and <12.2I U/l for females ≥55 y. CONCLUSION: The Immulite 1000 hCG assay can accurately quantify hCG in urine.

Progestogens for preterm birth prevention: a systematic review and meta-analysis.

OBJECTIVE: We systematically reviewed the effectiveness of progestogens for prevention of preterm birth among women with prior spontaneous preterm birth, multiple gestations, preterm labor, short cervix, or other indications. DATA SOURCES: We searched MEDLINE and EMBASE databases for English language articles published from January 1966 to October 2011. METHODS OF STUDY SELECTION: We excluded publications that were not randomized controlled trials or had fewer than 20 participants, identifying 34 publications, of which 19 contained data for Bayesian meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Two reviewers independently extracted data and assigned overall quality ratings based on predetermined criteria. Among women with prior preterm birth and a singleton pregnancy (five randomized controlled trials), progestogen treatment decreased the median risk of preterm birth by 22% (relative risk [RR] 0.78, 95% Bayesian credible interval 0.68-0.88) and neonatal death by 42% (RR 0.58, 95% Bayesian credible interval 0.27-0.98). The evidence suggests progestogen treatment does not prevent prematurity (RR 1.02, 95% Bayesian credible interval 0.87-1.17) or neonatal death (RR 1.44, 95% Bayesian credible interval 0.46-3.18) in multiple gestations. Limited evidence suggests progestogen treatment may prevent prematurity in women with preterm labor (RR 0.62, 95% Bayesian credible interval 0.47-0.79) and short cervix (RR 0.52, 95% Bayesian credible interval 0.36-0.70). Across indications, evidence about maternal, fetal, or neonatal health outcomes, other than reducing preterm birth and neonatal mortality, is inconsistent, insufficient, or absent. CONCLUSION: Progestogens prevent preterm birth when used in singleton pregnancies for women with a prior preterm birth. In contrast, evidence suggests lack of effectiveness for multiple gestations. Evidence supporting all other uses is insufficient to guide clinical care. Overall, clinicians and patients lack longer-term information to understand whether intervention has the ultimately desired outcome of preventing morbidity and promoting normal childhood development.