Performance of a Modern Glucose Meter in ICU and General Hospital Inpatients: 3 Years of Real-World Paired Meter and Central Laboratory Results.

OBJECTIVE: Due to accuracy concerns, the Food and Drug Administration issued guidances to manufacturers that resulted in Center for Medicare and Medicaid Services stating that the use of meters in critically ill patients is "off-label" and constitutes "high complexity" testing. This is causing significant workflow problems in ICUs nationally. We wished to determine whether real-world accuracy of modern glucose meters is worse in ICU patients compared with non-ICU inpatients. DESIGN: We reviewed glucose results over the preceding 3 years, comparing results from paired glucose meter and central laboratory tests performed within 60 minutes of each other in ICU versus non-ICU settings. SETTING: Seven ICU and 30 non-ICU wards at a 1,300-bed academic hospital in the United States. SUBJECTS: A total of 14,763 general medicine/surgery inpatients and 20,970 ICU inpatients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compared meter results with near simultaneously performed laboratory results from the same patient by applying the 2016 U.S. Food and Drug Administration accuracy criteria, determining mean absolute relative difference and examining where paired results fell within the Parkes consensus error grid zones. A higher percentage of glucose meter results from ICUs than from non-ICUs passed 2016 Food and Drug Administration accuracy criteria (p < 10) when comparing meter results with laboratory results. At 1 minute, no meter result from ICUs posed dangerous or significant risk by error grid analysis, whereas at 10 minutes, less than 0.1% of ICU meter results did, which was not statistically different from non-ICU results. CONCLUSIONS: Real-world accuracy of modern glucose meters is at least as accurate in the ICU setting as in the non-ICU setting at our institution.

Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, syndrome of excessive and ineffective activation of the immune system. The majority of the reported data on HLH is from pediatric patients and lacks specificity. This makes HLH diagnosis challenging especially in adults where HLH is triggered by many conditions and can resemble many disease entities. Elevated ferritin is one of the diagnostic criteria for HLH. We determined the conditions associated with elevated ferritin at our medical center to assess how specific ferritin is for predicting HLH. We retrospectively reviewed all ferritin results >10,000 µg/L in pediatric and adult patients. The most common condition associated with elevated ferritin was hematologic malignancy in adults (25.7%) and HLH in pediatric patients (48.9%). HLH was diagnosed in 14.2% of adults and 48.9% of children with ferritin >10,000 µg/L. Hyperferritinemia occurs in a variety of conditions and is not specific for adult or pediatric HLH. Common causes of elevated ferritin should be considered before entertaining the possibility of HLH, especially in adult patients.

High-sensitivity Cardiac Troponin Elevation after Electroconvulsive Therapy: A Prospective, Observational Cohort Study.

BACKGROUND: While electroconvulsive therapy is widely regarded as a lifesaving and safe procedure, evidence regarding its effects on myocardial cell injury is sparse. The objective of this investigation was to determine the incidence and magnitude of new cardiac troponin elevation after electroconvulsive therapy using a novel high-sensitivity cardiac troponin I assay. METHODS: This was a prospective cohort study in adult patients undergoing electroconvulsive therapy in a single academic center (up to three electroconvulsive therapy treatments per patient). The primary outcome was new high-sensitivity cardiac troponin I elevation after electroconvulsive therapy, defined as an increase of high-sensitivity cardiac troponin I greater than 100% after electroconvulsive therapy compared to baseline with at least one value above the limit of quantification (10 ng/l). Twelve-lead electrocardiogram and high-sensitivity cardiac troponin I values were obtained before and 15 to 30 min after electroconvulsive therapy; in a subset of patients, an additional 2-h high-sensitivity cardiac troponin I value was obtained. RESULTS: The final study population was 100 patients and a total of 245 electroconvulsive therapy treatment sessions. Eight patients (8 of 100; 8%) experienced new high-sensitivity cardiac troponin I elevation after electroconvulsive therapy with a cumulative incidence of 3.7% (9 of 245 treatments; one patient had two high-sensitivity cardiac troponin I elevations), two of whom had a non-ST-elevation myocardial infarction (incidence 2 of 245; 0.8%). Median high-sensitivity cardiac troponin I concentrations did not increase significantly after electroconvulsive therapy. Tachycardia and/or elevated systolic blood pressure developed after approximately two thirds of electroconvulsive therapy treatments. CONCLUSIONS: Electroconvulsive therapy appears safe from a cardiac standpoint in a large majority of patients. A small subset of patients with preexisting cardiovascular risk factors, however, may develop new cardiac troponin elevation after electroconvulsive therapy, the clinical relevance of which is unclear in the absence of signs of myocardial ischemia.

High-Sensitivity Cardiac Troponin T Improves the Diagnosis of Perioperative MI.

BACKGROUND: The diagnosis of myocardial infarction (MI) after noncardiac surgery has traditionally relied on using relatively insensitive contemporary cardiac troponin (cTn) assays. We hypothesized that using a recently introduced novel high-sensitivity cTnT (hscTnT) assay would increase the detection rate of perioperative MI. METHODS: In this ancillary study of the Vitamins in Nitrous Oxide trial, readjudicated incidence rates of myocardial injury (new isolated cTn elevation) and MI were compared when diagnosed by contemporary cTnI versus hscTnT. We probed various relative (eg, >50%) or absolute (eg, +5 ng/L) hscTnT change metrics. Inclusion criteria for this ancillary study were the presence of a baseline and at least 1 postoperative hscTnT value. RESULTS: Among 605 patients, 70 patients (12%) had electrocardiogram changes consistent with myocardial ischemia; 82 patients (14%) had myocardial injury diagnosed by contemporary cTnI, 31 (5.1%) of which had an adjudicated MI. After readjudication, 67 patients (11%) were diagnosed with MI when using hscTnT, a 2-fold increase. Incidence rates of postoperative myocardial injury ranged from 12% (n = 73) to 65% (n = 393) depending on the hscTnT metric used. Incidence rates of MI using various hscTnT change metrics and the presence of ischemic electrocardiogram changes, but without event adjudication, ranged from 3.6% (n = 22) to 12% (n = 74), a >3-fold difference. New postoperative hscTnT elevation, either by absolute or relative hscTnT change metric, was associated with an up to 5-fold increase in 6-month mortality. CONCLUSIONS: The use of hscTnT compared to contemporary cTnI increases the detection rate of perioperative MI by a factor of 2. Using different absolute or relative hscTnT change metrics may lead to under- or overdiagnosis of perioperative MI.

Improving Prediction of Postoperative Myocardial Infarction With High-Sensitivity Cardiac Troponin T and NT-proBNP.

BACKGROUND: This study sought to determine whether preoperatively measured high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) improve cardiac risk prediction in patients undergoing major noncardiac surgery compared with the standard risk indices. METHODS: In this ancillary study to the Vitamins in Nitrous Oxide trial, patients were included who had preoperative hs-cTnT and NT-proBNP measured (n = 572). Study outcome was the incidence of postoperative myocardial infarction (MI) within the first 3 postoperative days. hs-cTnT was considered elevated if >14 ng/L and NT-proBNP if >300 ng/L. Additional cutoff values were investigated on the basis of receiver operating characteristic statistics. Biomarker risk prediction was compared with Lee's Revised Cardiac Risk Index (RCRI) with the use of standard methods and net reclassification index. RESULTS: The addition of hs-cTnT (>14 ng/L) and NT-proBNP (>300 ng/L) to RCRI significantly improved the prediction of postoperative MI (event rate 30/572 [5.2%], Area under the receiver operating characteristic curve increased from 0.590 to 0.716 with a 0.66 net reclassification index [95% confidence interval 0.32-0.99], P < .001). The use of 108 ng/L as a cutoff for NT-proBNP improved sensitivity compared with 300 ng/L (0.87 vs 0.53). Sensitivity, specificity, positive, and negative predictive value for hs-cTnT were 0.70, 0.60, 0.09, and 0.97 and for NT-proBNP were 0.53, 0.68, 0.08, and 0.96. CONCLUSIONS: The addition of cardiac biomarkers hs-cTnT and NT-proBNP to RCRI improves the prediction of adverse cardiac events in the immediate postoperative period after major noncardiac surgery. The high negative predictive value of preoperative hs-cTnT and NT-proBNP suggest usefulness as a "rule-out" test to confirm low risk of postoperative MI.

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.

Recommendations for the Generation, Quantification, Storage, and Handling of Peptides Used for Mass Spectrometry-Based Assays.

BACKGROUND: For many years, basic and clinical researchers have taken advantage of the analytical sensitivity and specificity afforded by mass spectrometry in the measurement of proteins. Clinical laboratories are now beginning to deploy these work flows as well. For assays that use proteolysis to generate peptides for protein quantification and characterization, synthetic stable isotope-labeled internal standard peptides are of central importance. No general recommendations are currently available surrounding the use of peptides in protein mass spectrometric assays. CONTENT: The Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling, as well as approaches to the interpretation of the data generated by mass spectrometric protein assays. Additionally, the importance of carefully characterized reference materials-in particular, peptide standards for the improved concordance of amino acid analysis methods across the industry-is highlighted. The alignment of practices around the use of peptides and the transparency of sample preparation protocols should allow for the harmonization of peptide and protein quantification in research and clinical care.

Falsely Elevated Plasma Creatinine Due to an Immunoglobulin M Paraprotein.

The most common method for measuring plasma creatinine is based on its reaction with picric acid. However, enzymatic methods are becoming more popular due to improved specificity. We present a case of falsely elevated plasma creatinine values obtained by an enzymatic method that turned out to be due to a monoclonal immunoglobulin M (IgM) paraprotein. A 63-year-old woman evaluated for lung transplantation had falsely increased plasma creatinine levels (1.54-1.71mg/dL; corresponding to estimated glomerular filtration rates of 32-36 mL/min/1.73m2) as measured by the Roche Creatinine plus enzymatic assay when compared with the picric acid-based procedure and several other enzymatic methods, which gave plasma creatinine values of 0.7 to 0.8mg/dL. Serum protein electrophoresis revealed an IgM κ light chain paraprotein. Removal of high-molecular-weight (>30kDa) proteins by ultrafiltration reduced the patient's plasma creatinine level by the Roche enzymatic method to 0.7mg/dL. Addition of the patient's immunoglobulin fraction to plasma from other patients with normal plasma creatinine levels resulted in values that were increased by 0.58 to 0.62mg/dL. Furthermore, removal of non-IgM immunoglobulins with protein G-coupled beads did not eliminate the interference from the patient's plasma. Taken together, these studies demonstrate that falsely elevated plasma creatinine values by the Roche enzymatic method can be due to an IgM paraprotein.

Impact on Patient Management and Outcome of Switching between 2 Contemporary Sensitive Cardiac Troponin Assays.

BACKGROUND: Myocardial infarction is characterized by an increase of cardiac troponin I (cTnI) above the 99th percentile of a reference population. Our hospital switched from 1 contemporary cTnI assay to another and observed a doubling of cTnI results above the assays' respective 99th percentile cutoffs. We investigated the potential impact on inpatient management and outcomes. METHODS: We performed a retrospective cohort study of 45 498 individuals with ≥1 cTnI result between January 2013 and June 2014. The Dimension cTnI assay was used in 2013; the Abbott Architect cTnI assay was used in 2014. RESULTS: Before switching cTnI assays, 19.2% (4742/30 872) of patients had at least 1 of the first 3 cTnIs above the 99th percentile (0.07 µg/L). After switching to the Architect cTnI assay, 31.4% (4034/14 626) of patients had at least 1 cTnI above the 99th percentile (0.03 µg/L). This increase was due to the difference in the assays' 99th percentile cutoffs. Having an increased cTnI reported on the Architect assay that would not have been reported as such on the Dimension assay (0.03-0.06 µg/L) correlated with increased inpatient mortality, length of stay, non-ST elevation myocardial infarction diagnosis, therapeutic heparin use, and percutaneous coronary intervention, relative to individuals with cTnI <0.03 µg/L. CONCLUSIONS: The changes observed in patient outcomes and management were likely due to the increased sensitivity and lower 99th percentile cutoff of the Architect assay. It is important to recognize the potential impact that differences in sensitivity and assay configuration may have on patient management.

High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery.

BACKGROUND: Perioperative myocardial infarction (MI) is a serious complication after noncardiac surgery. We hypothesized that preoperative cardiac troponin T detected with a novel high-sensitivity (hs-cTnT) assay will identify patients at risk for acute MI and long-term mortality after major noncardiac surgery. METHODS: This was a prospective cohort study within the VINO trial (n = 608). Patients had been diagnosed with or had multiple risk factors for coronary artery disease and underwent major noncardiac surgery. Cardiac troponin I (contemporary assay) and troponin T (high-sensitivity assay) and 12-lead electrocardiograms were obtained before and immediately after surgery and on postoperative days 1, 2, and 3. RESULTS: At baseline before surgery, 599 patients (98.5%) had a detectable hs-cTnT concentration, and 247 (41%) were >14 ng/L (99th percentile). After surgery, 497 patients (82%) had a rise in hs-cTnT (median change in hs-cTnT +2.7 ng/L [interquartile range 0.7-6.8]). During the first 3 postoperative days, there were 9 patients (2.5%) with a preoperative hs-cTnT <14 ng/L with acute MI, compared with 21 patients (8.6%) with a preoperative hs-cTnT >14 ng/L (odds ratio 3.67, 95% CI 1.65-8.15). During long-term follow-up, 80 deaths occurred. The 3-year mortality rate was 11% in patients with a preoperative hs-cTnT concentration <14 ng/L compared with 25% in patients with a preoperative hs-cTnT >14 ng/L (adjusted hazard ratio 2.17, 95% CI 1.19-3.96). CONCLUSIONS: In this cohort of high-risk patients, preoperative hs-cTnT concentrations were significantly associated with postoperative MI and long-term mortality after noncardiac surgery.

Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial.

BACKGROUND: Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C gene variant. In this randomized controlled trial, the authors sought to determine whether patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and whether this risk could be mitigated by B-vitamins. METHODS: The authors randomized adult patients with cardiac risk factors undergoing noncardiac surgery, to receive nitrous oxide plus intravenous B-vitamins before and after surgery, or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I increase within the first 72 h after surgery. RESULTS: A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n=98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild-type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85-1.07; P=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78 to 1.32; P=0.91). CONCLUSIONS: Neither MTHFR C677T and A1298C gene variant, nor acute homocysteine increase are associated with perioperative cardiac troponin increase after nitrous oxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin I increase.

Clinical review: Consensus recommendations on measurement of blood glucose and reporting glycemic control in critically ill adults.

The management reporting and assessment of glycemic control lacks standardization. The use of different methods to measure the blood glucose concentration and to report the performance of insulin treatment yields major disparities and complicates the interpretation and comparison of clinical trials. We convened a meeting of 16 experts plus invited observers from industry to discuss and where possible reach consensus on the most appropriate methods to measure and monitor blood glucose in critically ill patients and on how glycemic control should be assessed and reported. Where consensus could not be reached, recommendations on further research and data needed to reach consensus in the future were suggested. Recognizing their clear conflict of interest, industry observers played no role in developing the consensus or recommendations from the meeting. Consensus recommendations were agreed for the measurement and reporting of glycemic control in clinical trials and for the measurement of blood glucose in clinical practice. Recommendations covered the following areas: How should we measure and report glucose control when intermittent blood glucose measurements are used? What are the appropriate performance standards for intermittent blood glucose monitors in the ICU? Continuous or automated intermittent glucose monitoring - methods and technology: can we use the same measures for assessment of glucose control with continuous and intermittent monitoring? What is acceptable performance for continuous glucose monitoring systems? If implemented, these recommendations have the potential to minimize the discrepancies in the conduct and reporting of clinical trials and to improve glucose control in clinical practice. Furthermore, to be fit for use, glucose meters and continuous monitoring systems must match their performance to fit the needs of patients and clinicians in the intensive care setting.