Should we depend on reference intervals from manufacturer package inserts? Comparing TSH and FT4 reference intervals from four manufacturers with results from modern indirect methods and the direct method.

OBJECTIVES: Correct interpretation of thyroid function tests relies on correct reference intervals (RIs) for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). ISO15189 mandates periodic verification of RIs, but laboratories struggle with cost-effective approaches. We investigated whether indirect methods (utilizing historical laboratory data) could replace the direct approach (utilizing healthy reference individuals) and compared results with manufacturer-provided RIs for TSH and FT4. METHODS: We collected historical data (2008-2022) from 13 Dutch laboratories to re-establish RIs by employing indirect methods, TMC (for TSH) and refineR (for FT4). Laboratories used common automated platforms (Roche, Abbott, Beckman or Siemens). Indirect RIs (IRIs) were determined per laboratory per year and clustered per manufacturer (>1.000.000 data points per manufacturer). Direct RIs (DRIs) were established in 125 healthy individuals per platform. RESULTS: TSH IRIs remained robust over the years for all manufacturers. FT4 IRIs proved robust for three manufacturers (Roche, Beckman and Siemens), but the IRI upper reference limit (URL) of Abbott showed a decrease of 2 pmol/L from 2015. Comparison of the IRIs and DRIs for TSH and FT4 showed close agreement using adequate age-stratification. Manufacturer-provided RIs, notably Abbott, Roche and Beckman exhibited inappropriate URLs (overall difference of 0.5-1.0 µIU/mL) for TSH. For FT4, the URLs provided by Roche, Abbott and Siemens were overestimated by 1.5-3.5 pmol/L. CONCLUSIONS: These results underscore the importance of RI verification as manufacturer-provided RIs are often incorrect and RIs may not be robust. Indirect methods offer cost-effective alternatives for laboratory-specific or platform-specific verification of RIs.

Thiamine Levels During Intensive Insulin Therapy in Critically Ill Patients.

INTRODUCTION: Thiamine is an essential cofactor in carbohydrate metabolism, and deficiency can therefore cause various organ dysfunctions. Little is known about the prevalence and possible worsening of thiamine deficiency in critically ill patients. In this study, we investigated the prevalence of thiamine deficiency at admission to the intensive care unit (ICU) and hypothesized that intensive insulin therapy, aimed at regulating glucose levels, increases thiamine utilization and therefore might cause or worsen deficiency in patients with limited thiamine stores. MATERIALS AND METHODS: An observational prospective cohort study was carried out in a medical-surgical ICU in a general teaching hospital in Apeldoorn, the Netherlands. All adults who were treated during that time with intensive insulin therapy were included. Deficiency was defined as a thiamine level <100 nmol/L. No thiamine supplementation was administered except for normal amounts present in standard enteral feeding. RESULTS: A total of 58 patients were available for analysis. Median thiamine level at admission was 111 nmol/L. Deficiency was present in 39.7% of patients and was significantly associated with the presence of gastrointestinal pathology and with recent surgery. Thiamine levels increased a median of 14 nmol/L in 48 hours. Only 3.4% of patients showed a predefined relevant decline in thiamine levels. CONCLUSION: Intensive insulin therapy does not appear to cause or worsen thiamine deficiency. However, based on the high prevalence of deficiency at admission, it might be warranted to supplement thiamine in all patients admitted to the ICU, especially when there is an underlying gastrointestinal disease or recent surgery.

Risk Factors for Recurrence of Benign Paroxysmal Positional Vertigo: A Prospective Study.

OBJECTIVES: Benign paroxysmal positional vertigo (BPPV) can be treated successfully in most cases. However, recurrences are common. We aimed to prospectively investigate demographic and clinical risk factors for BPPV recurrence. Our second aim was to investigate whether seasonality affects recurrences. METHODS: We recruited adult Dutch patients presenting at our dizziness clinic with a diagnosis of definite or possible BPPV for a prospective observational study with 1-year follow-up. Factors collected from patient history and questionnaires were age, sex, ethnicity, previous treatment for BPPV, duration of BPPV symptoms, number of treatment sessions for the initial BPPV episode, the affected canal, recent head trauma, and a history of vestibular neuritis, Menière's disease, (vestibular) migraine, gout, diabetes mellitus, and chronic renal failure. Factors derived from blood samples were uric acid, glycated hemoglobin, and 25-hydroxyvitamin D. RESULTS: We included 139 subjects with a mean age of 65 (SD, 13) years, of whom 70% was female. A total of 48 subjects (34.5%) suffered from at least one recurrence during the 1-year follow-up. Independent risk factors for recurrence of BPPV were "multiple treatment sessions for the initial BPPV episode" (incidence rate ratio, 1.74; 95% confidence interval 1.06-2.85; p = 0.027) and history of gout (incidence rate ratio, 1.90; 95% confidence interval, 1.01-3.57; p = 0.045). CONCLUSION: One-third of patients presenting in a tertiary dizziness clinic develop at least one recurrence of BPPV within 1 year. Multiple treatment sessions and a history of gout are independent risk factors for recurrence.

Age-specific reference intervals for TSH and FT4 to optimize diagnosis of thyroid disease.

Background Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, Beckman Coulter). Retrospective data (2008-2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2-20 years by 2-year categories and decade categories between 20 and 100 years. Results We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits (LRLs) were higher in early childhood and decreased towards adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onwards. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data is less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation.

INTRODUCTION: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. OBJECTIVE: To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. DESIGN, SETTING, AND PATIENTS: Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. RESULTS: Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. CONCLUSION: In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation.