Brad S. Karon

Can Serum β-Hydroxybutyrate Be Used to Diagnose Diabetic Ketoacidosis?

OBJECTIVE—Current criteria for the diagnosis of diabetic ketoacidosis (DKA) are limited by their nonspecificity (serum bicarbonate [HCO3] and pH) and qualitative nature (the presence of ketonemia/ketonuria). The present study was undertaken to determine whether quantitative measurement of a ketone body anion could be used to diagnose DKA. RESEARCH DESIGN AND METHODS—A retrospective review of records from hospitalized diabetic patients was undertaken to determine the concentration of serum β-hydroxybutyrate (βOHB) that corresponds to a HCO3 level of 18 mEq/l, the threshold value for diagnosis in recently published consensus criteria. Simultaneous admission βOHB and HCO3 values were recorded from 466 encounters, 129 in children and 337 in adults. RESULTS—A HCO3 level of 18 mEq/l corresponded with βOHB levels of 3.0 and 3.8 mmol/l in children and adults, respectively. With the use of these threshold βOHB values to define DKA, there was substantial discordance (∼≥20%) between βOHB and conventional diagnostic criteria using HCO3, pH, and glucose. In patients with DKA, there was no correlation between HCO3 and glucose levels on admission and a significant but weak correlation between βOHB and glucose levels (P < 0.001). CONCLUSIONS—Where available, serum βOHB levels ≥3.0 and ≥3.8 mmol/l in children and adults, respectively, in the presence of uncontrolled diabetes can be used to diagnose DKA and may be superior to the serum HCO3 level for that purpose. The marked variability in the relationship between βOHB and HCO3 is probably due to the presence of other acid-base disturbances, especially hyperchloremic, nonanion gap acidosis.OBJECTIVE Current criteria for the diagnosis of diabetic ketoacidosis (DKA) are limited by their nonspecificity (serum bicarbonate [HCO(3)] and pH) and qualitative nature (the presence of ketonemia/ketonuria). The present study was undertaken to determine whether quantitative measurement of a ketone body anion could be used to diagnose DKA. RESEARCH DESIGN AND METHODS A retrospective review of records from hospitalized diabetic patients was undertaken to determine the concentration of serum beta-hydroxybutyrate (betaOHB) that corresponds to a HCO(3) level of 18 mEq/l, the threshold value for diagnosis in recently published consensus criteria. Simultaneous admission betaOHB and HCO(3) values were recorded from 466 encounters, 129 in children and 337 in adults. RESULTS A HCO(3) level of 18 mEq/l corresponded with betaOHB levels of 3.0 and 3.8 mmol/l in children and adults, respectively. With the use of these threshold betaOHB values to define DKA, there was substantial discordance (approximately > or = 20%) between betaOHB and conventional diagnostic criteria using HCO(3), pH, and glucose. In patients with DKA, there was no correlation between HCO(3) and glucose levels on admission and a significant but weak correlation between betaOHB and glucose levels (P < 0.001). CONCLUSIONS Where available, serum betaOHB levels > or = 3.0 and > or = 3.8 mmol/l in children and adults, respectively, in the presence of uncontrolled diabetes can be used to diagnose DKA and may be superior to the serum HCO(3) level for that purpose. The marked variability in the relationship between betaOHB and HCO(3) is probably due to the presence of other acid-base disturbances, especially hyperchloremic, nonanion gap acidosis.

Accuracy of Roche Accu-Chek Inform Whole Blood Capillary, Arterial, and Venous Glucose Values in Patients Receiving Intensive Intravenous Insulin Therapy After Cardiac Surgery

Intravenous insulin protocols are increasingly common in the intensive care unit to maintain normoglycemia. Little is known about the accuracy of point-of-care glucometers for measuring glucose in this patient population or the impact of sample source (capillary, arterial, or venous whole blood) on the accuracy of glucometer results. We compared capillary, arterial, and venous whole blood glucose values with laboratory plasma glucose values in 20 patients after cardiac surgery. All 4 samples (capillary, arterial, and venous whole blood and laboratory plasma glucose) were analyzed hourly for the first 5 hours during intravenous insulin therapy in the intensive care unit. There were no significant differences between median capillary whole blood (149 mg/dL [8.3 mmol/L]) and laboratory plasma (151 mg/dL [8.4 mmol/L]) glucose levels. The median arterial (161 mg/dL [8.9 mmol/L]) and venous (162 mg/dL [9.0 mmol/L]) whole blood glucose levels were significantly higher than the median laboratory plasma glucose level. Capillary whole blood glucose levels correlate most closely with laboratory plasma glucose levels in patients receiving intensive intravenous insulin therapy after cardiac surgery.

Glucose Meter Performance Criteria for Tight Glycemic Control Estimated by Simulation Modeling

BACKGROUND Glucose meter analytical performance criteria required for safe and effective management of patients on tight glycemic control (TGC) are not currently defined. We used simulation modeling to relate glucose meter performance characteristics to insulin dosing errors during TGC. METHODS We used 29,920 glucose values from patients on TGC at 1 institution to represent the expected distribution of glucose values during TGC, and we used 2 different simulation models to relate glucose meter analytical performance to insulin dosing error using these 29,920 initial glucose values and assuming 10%, 15%, or 20% total allowable error (TEa) criteria. RESULTS One-category insulin dosing errors were common under all error conditions. Two-category insulin dosing errors occurred more frequently when either 20% or 15% TEa was assumed compared with 10% total error. Dosing errors of 3 or more categories, those most likely to result in hypoglycemia and thus patient harm, occurred infrequently under all error conditions with the exception of 20% TEa. CONCLUSIONS Glucose meter technologies that operate within a 15% total allowable error tolerance are unlikely to produce large (>or=3-category) insulin dosing errors during TGC. Increasing performance to 10% TEa should reduce the frequency of 2-category insulin dosing errors, although additional studies are necessary to determine the clinical impact of such errors during TGC. Current criteria that allow 20% total allowable error in glucose meters may not be optimal for patient management during TGC.

Comparison of Lactate Values Between Point-of-Care and Central Laboratory Analyzers

Measurement of lactate levels is important in the care of critically ill adult and pediatric patients. We compared 3 whole blood lactate methods (Radiometer ABL 725, Radiometer Medical A/S, Bronshoj, Denmark; i-STAT, i-STAT, East Windsor, NJ; and Nova Lactate Plus, Nova Biomedical, Waltham, MA) with 2 plasma-based methods (Roche Integra, Roche Diagnostics, Indianapolis, IN; and Vitros, Ortho Clinical Diagnostics, Rochester, NY). The Vitros LAC slide assay was used as the reference method. Results were compared by least squares regression and Bland-Altmann plots and by comparing concordance within clinically relevant lactate ranges. Correlation between lactate methods was good with slopes between 0.87 and 1.06 and intercepts of 0.9 to 1.8 mg/dL (0.1-0.2 mmol/L) of lactate for all 4 methods compared with the Vitros. At high (>54.1 mg/dL [6 mmol/L]) lactate values, the Radiometer and i-STAT methods reported lower lactate results compared with the Vitros and Integra. The Nova analyzer reported higher lactate results than either the Vitros or Integra. The negative bias in i-STAT and Radiometer results may confound the interpretation of patient condition if multiple methods are used within the same institution.

Temporal sequence of major biochemical events during Blood Bank storage of packed red blood cells

BACKGROUND We used sensitive spectroscopic techniques to measure changes in Band 3 oligomeric state during storage of packed red blood cells (RBC); these changes were compared to metabolic changes, RBC morphology, cholesterol and membrane protein loss, phospholipid reorganisation of the RBC membrane, and peroxidation of membrane lipid. The aim of the study was to temporally sequence major biochemical events occurring during cold storage, in order to determine which changes may underlie the structural defects in stored RBC. MATERIALS AND METHODS Fifteen RBC units were collected from normal volunteers and stored under standard blood bank conditions; both metabolic changes and lipid parameters were measured by multiple novel assays including a new mass spectrometric measurement of isoprostane (lipid peroxidation) and flow cytometric assessment of CD47 expression. Band 3 oligomeric state was assessed by time-resolved phosphorescence anisotropy, and RBC morphology by microscopy of glutaraldehyde-fixed RBC. RESULTS Extracellular pH decreased and extracellular potassium increased rapidly during cold storage. Band 3 on the RBC membrane aggregated into large oligomers early in the storage period and coincident with changes in RBC morphology. Membrane lipid changes, including loss of unesterified cholesterol, lipid peroxidation and expression of CD47, also changed early during the storage period. In contrast loss of acetylcholinesterase activity and haemolysis of RBC occurred late during storage. DISCUSSION Our results demonstrate that changes in the macromolecular organisation of membrane proteins on the RBC occur early in storage and suggest that lipid peroxidation and/or oxidative damage to the membrane are responsible for irreversible morphological changes and loss of function during red cell storage.

Anesthetics alter the physical and functional properties of the Ca-ATPase in cardiac sarcoplasmic reticulum.

We have studied the effects of the local anesthetic lidocaine, and the general anesthetic halothane, on the function and oligomeric state of the CA-ATPase in cardiac sarcoplasmic reticulum (SR). Oligomeric changes were detected by time-resolved phosphorescence anisotropy (TPA). Lidocaine inhibited and aggregated the Ca-ATPase in cardiac SR. Micromolar calcium or 0.5 M lithium chloride protected against lidocaine-induced inhibition, indicating that electrostatic interactions are essential to lidocaine inhibition of the Ca-ATPase. The phospholamban (PLB) antibody 2D12, which mimics PLB phosphorylation, had no effect on lidocaine inhibition of the Ca-ATPase in cardiac SR. Inhibition and aggregation of the Ca-ATPase in cardiac SR occurred at lower concentrations of lidocaine than necessary to inhibit and aggregate the Ca-ATPase in skeletal SR, suggesting that the cardiac isoform of the enzyme has a higher affinity for lidocaine. Halothane inhibited and aggregated the Ca-ATPase in cardiac SR. Both inhibition and aggregation of the Ca-ATPase by halothane were much greater in the presence of PLB antibody or when PLB was phosphorylated, indicating a protective effect of PLB on halothane-induced inhibition and aggregation. The effects of halothane on cardiac SR are opposite from the effects of halothane observed in skeletal SR, where halothane activates and dissociates the Ca-ATPase. These results underscore the crucial role of protein-protein interactions on Ca-ATPase regulation and anesthetic perturbation of cardiac SR.

Aspirin Responsiveness in Healthy Volunteers Measured with Multiple Assay Platforms

BACKGROUND We evaluated the sensitivity, precision, and concordance of 4 assays designed to detect aspirin responsiveness or resistance. METHODS Twenty-nine healthy laboratory volunteers took 80 mg aspirin for 7 days, and a subset of volunteers took 325 mg aspirin for an additional 7 days. We measured platelet function by light transmission aggregometry with arachidonic acid, PFA-100, and VerifyNow. PFA-100 and VerifyNow assays were performed in duplicate to assess method imprecision. Some volunteers had samples taken within 2-4 h of the final dose of aspirin and again within 20-24 h of the final dose. We measured urinary 11-dehydro-thromboxane B(2) at baseline and after 80 or 325 mg aspirin. RESULTS No volunteers were nonresponsive to aspirin therapy as measured by the PFA-100. One of 29 participants demonstrated lack of response to aspirin as measured by VerifyNow and urinary 11-dehydro-thromboxane B(2); 2 of 29 demonstrated lack of response as measured by light transmission aggregometry. Imprecision was <10% for the PFA-100 and VerifyNow. Concordance was high (>90%) between all assays. Neither aspirin dose (80 vs 325 mg) nor timing between final dose of aspirin and blood draw (2-4 vs 20-24 h) affected any of the assays. CONCLUSIONS Light transmission aggregometry, PFA-100, VerifyNow, and urinary 11-dehydro-thromboxane B(2) are all sensitive to the effects of aspirin in healthy individuals. Variables such as aspirin dose, timing between final dose of aspirin and blood collection, and imprecision do not affect the ability of the assays to detect aspirin effect on platelet function.

Leadership and management training for residents and fellows: a curriculum for future medical directors.

CONTEXT Management of laboratories and pathology practices is increasingly complex. Residents and fellows in laboratory medicine and pathology need more structured curricula in leadership and management (L&M) training to function as medical and laboratory directors. OBJECTIVE To define a curriculum that provides basic competency in L&M for residents and fellows in pathology. DESIGN A year-long formal L&M course included didactic lectures, interactive sessions, case scenarios, team-building exercises, formal team presentations (capstone project), and precourse and postcourse assessment of L&M knowledge. The curriculum meets requirements of American College of Graduate Medical Education and supports goals for leadership training of the College of American Pathologists. Participants evaluated (5-point scale) the content and speakers of all sessions. Trainees were evaluated after considering postcourse examination results, quality of the capstone presentation, and a global assessment. RESULTS The 5 non-capstone sessions received evaluation scores ranging from 4.4 (informatics) to 5 (L&M basics). Postcourse test scores showed significant improvement when compared with the pretest scores for the 2003-2004 and 2004-2005 trainee cohorts. CONCLUSIONS Short-term results indicate that the course described improves trainee knowledge of L&M issues.

Why is everyone so excited about thromboelastrography (TEG)

Thromboelastrography (TEG) is one of the most common whole-blood viscoelastic coagulation tests used in clinical laboratories and at the point of care. TEG provides information on coagulation defects that are often difficult to detect using routine laboratory tests such as activated partial prothrombin time or prothrombin time. In certain critically ill patient populations, the use of TEG instead of or in addition to routine laboratory coagulation tests has been shown to improve outcomes or reduce transfusion requirements. However, TEG and other viscoelastic coagulation tests are affected by unique pre-analytic and analytic variables that do not impact other common laboratory coagulation tests. In this review the underlying principles, clinical applications, and laboratory aspects of TEG testing are discussed.

Comparison and validation of point of care lactate meters as a replacement for fetal pH measurement

OBJECTIVE To validate a point of care lactate device to replace fetal pH measurement. STUDY DESIGN AND METHODS Cord blood samples drawn immediately following delivery were tested on the Nova Lactate Plus and ARKRAY Lactate Pro, the Corometrics 220 pH System, and the Vitros chemistry analyzer (used as lactate reference). RESULTS Nova demonstrated a constant positive bias relative to the lactate reference method; while the Lactate Pro correlated well with the reference method up to 6 mmol/L. Receiver operating characteristic (ROC) curve analysis showed optimal sensitivity and specificity for predicting pH<7.20 at lactate values of 6.8 mmol/L for the Nova and 4.8 mmol/L for the Lactate Pro. CONCLUSION Using Lactate Pro the best cut-off for predicting pH< or =7.20 was 4.8 mM; which coincides with current clinical cut-offs. Thus any lactate device that correlates well with the laboratory reference method can be used with a clinical cut-off of 4.8 mmol/L.