Stephen E. Kahn

Roadmap for Harmonization of Clinical Laboratory Measurement Procedures

Results between different clinical laboratory measurement procedures (CLMP) should be equivalent, within clinically meaningful limits, to enable optimal use of clinical guidelines for disease diagnosis and patient management. When laboratory test results are neither standardized nor harmonized, a different numeric result may be obtained for the same clinical sample. Unfortunately, some guidelines are based on test results from a specific laboratory measurement procedure without consideration of the possibility or likelihood of differences between various procedures. When this happens, aggregation of data from different clinical research investigations and development of appropriate clinical practice guidelines will be flawed. A lack of recognition that results are neither standardized nor harmonized may lead to erroneous clinical, financial, regulatory, or technical decisions. Standardization of CLMPs has been accomplished for several measurands for which primary (pure substance) reference materials exist and/or reference measurement procedures (RMPs) have been developed. However, the harmonization of clinical laboratory procedures for measurands that do not have RMPs has been problematic owing to inadequate definition of the measurand, inadequate analytical specificity for the measurand, inadequate attention to the commutability of reference materials, and lack of a systematic approach for harmonization. To address these problems, an infrastructure must be developed to enable a systematic approach for identification and prioritization of measurands to be harmonized on the basis of clinical importance and technical feasibility, and for management of the technical implementation of a harmonization process for a specific measurand.

Analytic bias among certified methods for the measurement of hemoglobin A1c: a cause for concern?

We studied the magnitude, significance, and origin of an analytic bias that emerged between our point-of-care (POC) and our central laboratory (CL) methods for the measurement of hemoglobin A1c (HbA1c) and evaluated the analytic accuracy of 7 commonly used HbA1c methods relative to the National Glycohemoglobin Standardization Program (NGSP) reference method. The POC and CL methods were compared by split-sample analysis of clinical specimens and time series analyses of the HbA1c results reported for a 33-month period. The relative accuracies of 7 HbA1c methods were evaluated using College of American Pathologists proficiency survey results. Long-term drifts in the CL- and POC-analyzed test results caused the median intermethod bias [(POC result)-(CL result)] to increase from -0.4% to -0.9% HbA1c. Systematic biases, drifts in analytic performance over time, and intermethod variability were frequently observed among the 7 NGSP-certified HbA1c methods. Intermethod variability is a potential source of inaccuracy whenever HbA1c results are interpreted relative to universal, fixed, clinical decision thresholds.

Myocardial injury in children with respiratory syncytial virus infection.

Objective Respiratory syncytial virus (RSV) infection is associated with a number of extrapulmonary manifestations, including a sepsis-like syndrome characterized by any combination of hypothermia, fever, apnea, hypovolemia, and myocardial dysfunction. We hypothesized that RSV can have a direct injurious effect on the myocardium of infants and children that can be detected by the presence of cardiac troponin I (cTnI), a highly sensitive and specific marker of myocardial injury, in the blood of patients infected with the virus. Design Serial cTnI measurements were obtained from patients admitted with documented RSV infection to the pediatric intensive care unit (PICU). Participants Data were collected and analyzed from 22 RSV infected patients and 11 control patients. Results Elevated levels of cTnI were detected in 54.5% (12/22) of the study population during their PICU admission. The average cTnI level was significantly higher in the RSV infected group than in controls. There was a significant association between the presence of a positive troponin assay and the occurrence of a cardiovascular event, the need for inotropic support, and the requirement of mechanical ventilation. Patients who required inotropic support had a significantly higher cTnI level than the rest of the study population. Conclusion A large percentage of children admitted to the PICU with RSV infection have myocardial damage as detected by the use of commercially available troponin assays. Additionally, in a portion of these patients, this damage is clinically significant, leading to cardiovascular instability and the need for inotropic support.

Tryptophan distribution and metabolism in experimental chronic renal insufficiency

Several aspects of tryptophan distribution and metabolism in chronic renal insufficiency (CRI) were investigated in a rat model prepared by partial nephrectomy. Partially nephrectomized (pNx) rats with a moderate degree of CRI demonstrated a 40% decrease in plasma total tryptophan concentration between 5 and 11 weeks after the acute reduction of renal functional mass. This decrease was accompanied by hypoalbuminemia, polyuria, albuminuria, and tryptophanuria. After 5 weeks of sustained plasma total tryptophan deficiency (from Week 6 to Week 11), the plasma free tryptophan concentration, the plasma concentrations of large neutral amino acids, and the tryptophan levels in red cells, liver, and kidney of the pNx rats were similar to those of the controls. However, evidence for abnormal brain tryptophan metabolism in pNx rats after 11 weeks of CRI included 16% reductions of tryptophan levels in the midbrain and pons and 65% increases in the serotonin contents of the hypothalamus and medulla. Monoamine oxidase activities in hypothalamus and cerebellum of pNx rats were the same as those of the controls. These studies indicate that tryptophanuria is an important factor in the development of the plasma tryptophan deficiency in the pNx model. In addition, the results support the hypothesis that regional abnormalities in tryptophan metabolism contribute to the neurological and neuroendocrine dysfunction of CRI.

How accurate is glucose analysis in the presence of multiple interfering substances in the neonate? (glucose analysis and interfering substances)

Whole blood glucose testing by reagent sticks is inaccurate at low plasma glucose concentrations and with varying hemalocrit. Both conditions are frequently seen in newborn infants. Therefore plasma glucose analysis is the preferred method for newborn glucose monitoring. We encountered unanticipated difficulties in plasma glucose measurement by the automated hexokinase method caused by the combinations of plasma free hemoglobin, bilirubin, and plasma triglycerides, which are frequently elevated in newborn plasma. We determined the adverse effects of various combinations of these interfering substances on glucose analysis by the hexokinase method and demonstrated that accurate analysis is possible by a 1:1 plasma dilution only at high plasma glucose levels but not at the more critical low plasma glucose concentration. The dilution reduced the number of repeat specimen required in newborns. But 1:1 plasma dilution overestimated the glucose levels at low plasma glucose values, and therefore this automated hexokinase method is not suitable for glucose analysis in the newborn. Glucose‐oxidase remains the method of choice for plasma glucose analysis in neonates. This information is important because using this hexokinase methodology, one might miss hypoglycemia in the newborn.

Treatment of US crotalidae bites : Comparisons of serum and globulin-based polyvalent and antigen-binding fragment antivenins

In the US, two antivenins are marketed for the treatment of snake envenomation. The horse-derived serum-globulin-based Antivenin (Crotalidae) Polyvalent (ACP) has been available since 1954. There are few data on the efficacy and incidence of adverse events that occur following the administration of ACP. Most of the data are retrospective, anecdotal, or case reports. In 2000, ovine-derived serum-globulin-based ACP (Crofab®) became available. Crofab® is said to cause fewer reactions than ACP, but there are few comparative data to substantiate this claim. Although both antivenins ameliorate the systemic symptoms following snake envenomation, the efficacy of either antivenin in decreasing oedema and swelling is unknown for a number of reasons. Clinical trials are small and have not included control arms. The degree of oedema, as well as the efficacy of the antivenin in decreasing oedema, may depend on the genera of the snake (usually unknown) that envenomated the patient. This article compares available data on clinical aspects of the two antivenins. More prospective data are needed to determine the comparative efficacy of the two antivenins, or the efficacy of Crofab® in preventing tissue oedema. There are still unanswered questions regarding the optimal dosing regimen of Crofab®.

Association of mild transient elevation of troponin I levels with increased mortality and major cardiovascular events in the general patient population

CONTEXT The prognostic value of mild elevation of cardiac-specific troponin I (cTnI) levels is poorly defined, which can make interpretation of such an elevation difficult. OBJECTIVE To study the prognostic value of transient mild elevation of cTnI levels in the hospitalized patient population. DESIGN We performed a case-control study that compared the outcome of patients hospitalized for any cause with at least 2 subsequent transient cTnI measurements of 0.1 ng/mL or higher and less than 1.5 ng/mL with matched controls with cTnI levels less than 0.1 ng/mL. A cohort of 118 patients (mean +/- SD age, 67.4 +/- 14.0 years; 35.6% men) was followed up for an average +/- SD of 11.9 +/- 7.9 months. Seventy-one cases were matched with 37 controls in terms of demographics, coronary artery disease risk factors, and reason for admission. End points were all-cause mortality and major cardiovascular end points, including cardiovascular mortality, myocardial infarction, and revascularization. RESULTS The total event rate was significantly increased in the case group compared with the control group at 12, 6, and 3 months (62.0% vs 24.3%, 59.2% vs 16.2%, and 47.9% vs 5.4%, respectively; P < .001). At 12, 6, and 3 months, the cases had a significant increase in all-cause mortality (43.7% vs 16.2%, 40.8% vs 8.1%, and 33.8% vs 0.0%, respectively; P = .005) and major cardiovascular end points (26.8% vs 8.1%, 26.8% vs 8.1%, and 21.1% vs 5.4%, respectively; P = .02) compared with controls. CONCLUSION Transient mild elevation of cTnI levels in hospitalized patients is associated with an increase in all-cause mortality and major cardiovascular complications. Such elevations of cTnI levels can be considered a marker for both all-cause and cardiovascular morbidity and mortality.

SERUM LIPID CONCENTRATIONS IN SIX CANID AND FOUR URSID SPECIES IN FOUR ZOOS

Abstract Serum lipid levels were measured in healthy captive wild canids and ursids, and the values were compared with previously published data. Serum lipid levels were evaluated in blood samples collected from eight African wild dogs (Lycaon pictus), three arctic foxes (Alopex lagopus), nine gray wolves (Canis lupus), four maned wolves (Chrysocyon brachyurus), two Mexican wolves (Canis lupus baleiyi), nine red wolves (Canis rufus), two brown bears (Ursus arctos), six polar bears (Ursus maritimus), six spectacled bears (Tremarctos ornatus), and five sun bears (Ursus malayanus). Samples were analyzed for total cholesterol, triacylglycerides, high-density lipoprotein–cholesterol, and low-density lipoprotein–cholesterol. Although the results showed a great variation among species, circulating lipids appeared especially high, sometimes extremely so, in the spectacled bears, polar bears, sun bears, and maned wolves compared with all other species sampled. The study provides a substantial basis for comparing lipid levels in presumed healthy animals and indicates a need for controlled study of the effects of diet on circulating lipid levels.

Early Recognition and Treatment of Sepsis After the Addition of Lactate to the Laboratory's Critical Result Call List.

Purpose: Screening of patients with sepsis is needed to increase recognition and allow for earlier interventions. There is no consensus on whether the addition of lactate to the critical result laboratory’s call list should be a standard practice. Materials and Methods: This was a retrospective cohort study that compared management and outcomes of patients with sepsis having lactate ≥4 mmol/L before (group 1) and after (group 2) the addition of a critical result threshold of lactate of ≥4 mmol/L to the critical result laboratory’s call list and its effects on time to antibiotics and intravenous fluids (IVFs). Results: One hundred twenty-one patients were included. Lactate was higher in group 1 (7.0 ± 4.3 vs 5.6 ± 2.0, P = 0.03). More patients in group 2 received hydrocortisone (1.9% vs 22.4%, P = .001). Hospital mortality, 30-day mortality, and 90-day mortality were significantly lower in group 2 (59.3% vs 32.8%, P = .003; 68.5% vs 37.3%, P ≤ .001; 68.5% vs 41.8%, P = .002). There were no significant differences in total volume of IVFs (2400.8 ± 1720.0 vs 2483.7 ± 2155.7, P = 0.83), time to start IVFs (184.0 ± 283.2 vs 115.6 ± 190.5, P = 0.27), or antibiotics (184.8 ± 187.1 vs 133.7 ± 137.4, P = 0.16). Conclusion: Addition of lactate to the critical result laboratory’s call list did not lead to a statistically significant improvement in time to IVFs or antibiotics, although the average time to antibiotics and IVFs decreased by 51.1 and 68.4 minutes, respectively. Hospital mortality, 30-day mortality, and 90-day mortality were lower in group 2, which may be, in part, due to increased recognition of severe sepsis by critical result notification and earlier intervention.