Guidelines and algorithms: perceptions of why and when they are successful and how to improve them.

Medicine is increasingly complex, a reality created by the explosion of knowledge during the last 50 years. The cost of applying this knowledge creates a daunting economic challenge. As a result, there has been a profusion of guidelines intended to influence medical practice. This report explores the interrelated issues and concepts that impact the value and success of guidelines. These include medical quality and error, compliance, and the impact on outcomes in an evidence-based medicine context. Lessons learned from previous guidelines must be understood in relation to human behavior. Legal implications of the guidelines must be considered because both an increase and a decrease in liability can be anticipated. Many products have been labeled "advocacy guidelines" with a negative context. They are believed to express motivation rather than optimizing care. The ideal of professionalism is challenged, and there is potential for the growing use of guidelines in enforcing punitive actions. Constructive experience has emphasized the appropriate required elements for practice guidelines: a systematic review of the literature, an assessment of the volume and level of the evidence, and development of a review process by an appropriate multidisciplinary group for consistency, clinical impact, and resource implications leading to clearly stated and reasonable recommendations. The dissemination of guidelines, beyond conventional publication in a journal, will impact the success of the intended outcomes. The exploitation of electronic avenues, including the Internet and the evolving interactive electronic medical record, seems to be essential for future success in these endeavors.

Discriminating between iron deficiency anemia and anemia of chronic disease using traditional indices of iron status vs transferrin receptor concentration.

We compared the ability of soluble serum transferrin receptor (TfR) concentration, quantified using the R&D Systems (Minneapolis, MN) enzyme-linked immunosorbent TfR assay, with other, more traditional indicators of iron status (total iron binding capacity [TIBC], mean corpuscular volume [MCV], percent transferrin saturation [%TS], RBC distribution width [RDW], and serum iron concentration [SIC]) for discriminating between patients with iron deficiency anemia (IDA) or anemia of chronic disease (ACD). The TfR concentration was determined in 72 serum samples selected from men and nonpregnant women classified biochemically on the basis of ferritin concentration as having IDA (n = 41) or ACD (n = 31). By using receiver operating characteristic curve analysis, the diagnostic accuracy of the various indicators of iron status that we evaluated for discriminating between IDA and ACD decreased in the following order: TIBC > TfR > MCV > (%TS = RDW) > SIC. There was no significant difference between the diagnostic accuracy of TIBC and TfR. Thus, the routine measurement of TfR offers no advantage over TIBC for discriminating between people with biochemically defined IDA or ACD.

Soluble transferrin receptor (sTfR) concentration quantified using two sTfR kits: analytical and clinical performance characteristics.

We compared the analytical and clinical performance characteristics of the Ramco and R&D Systems enzyme-linked immunosorbent assays (ELISAs) for quantifying serum levels of soluble transferrin receptor (sTfR). In addition, we determined both the number of samples required to determine the true individual mean sTfR concentration for a single individual and the critical difference (CD) between serial measurements that indicates a statistically significant change in sTfR concentration. sTfR concentration was determined in 127 serum samples selected retrospectively from males (n=32) and non-pregnant (n=40) and pregnant women (n=55). Intra- and inter-assay precision for both methods was good (CV values 5--10%) to excellent (CV values <5%) over a wide range of sTfR concentrations. Correlation between these methods was good (r=0.93); however, sTfR values by the R&D kit were approximately 2.9 times higher than values obtained using the Ramco kit on the same serum samples. Nevertheless, receiver-operator characteristic (ROC) curve analysis demonstrated that the diagnostic accuracy of both assays in discriminating between patients with iron-deficiency anemia (IDA) or anemia of chronic disease (ACD) was high (area-under-the-curve (AUC) values >0.95) and not significantly different (P=0.480). We determined that a minimum of 8 samples are required to determine an individual's true sTfR concentration, while a >40% difference between serial sTfR measurements would be required to indicate a statistically significant change in sTfR concentration. We concluded that both the Ramco and R&D Systems sTfR methods have similar analytical and clinical performance characteristics and were likely to be equally useful in discriminating between patients with biochemically defined IDA or ACD.

Effects of repeated electrical defibrillations on cardiac troponin I levels.

Multiple endocardial countershocks applied during intraoperative endocardial implantable cardioverter-defibrillator testing for the purpose of defibrillation threshold determination resulted in detectable myocardial injury in 5 of 12 patients, as indicated by elevations in cardiac troponin I levels. This injury was not associated with acute changes on the surface electrocardiogram.

Maternal cardiac troponin I levels during normal labor and delivery.

OBJECTIVE: Diagnosis of myocardial infarction in pregnant women on the basis of changes in biochemical markers is complicated by the release of some of these markers from noncardiac tissue sources. We compared troponin I levels with those of other markers in normal pregnant women. STUDY DESIGN: In 51 healthy women at term in labor, cardiac troponin I, myoglobin, creatine kinase, and creatine kinase MB levels were determined at admission, during the second stage of labor, and within 30 minutes, 12 hours, and 24 hours after delivery. RESULTS: Mean admission levels for all markers were below the upper limit of normal. Mean concentrations of myoglobin, creatine kinase, and creatine kinase MB mass were increased nearly twofold within 30 minutes after delivery. The highest level of troponin I (0.134 ng/mL) at all time points was below the cutoff value (0.15 ng/mL) for discriminating myocardial infarction. CONCLUSIONS: Because only troponin I levels remained undetectable during and after delivery, it is potentially the most useful biochemical marker for monitoring pregnant women for myocardial injury.

Biochemical advances in detection of the acute coronary syndromes: Implications for therapeutic decisions.

In this paper, I have attempted to place the evolving insights of the pathophysiology of coronary atherosclerosis in the context of the conventional perspective of clinical medicine. We strive to prevent death and to relieve suffering. Our clinical tools are critical but limited. Troponin, a biomarker of unprecedented organ specificity, in the context of the appropriate setting of new chest pain (or its equivalent syndrome), is an extraordinary aid to clinical diagnosis. Highly effective therapy is evolving which reduces loss of myocardium, undoubtedly reducing not only acute death but progression to congestive heart failure. Even if the newer therapies of the GpIIb/IIIa platelet antagonists and antithrombins are not yet widely employed, or may not be available to some physicians, the convincing demonstration of myocardial injury by troponin presents objective evidence to both the patient and the attending physician that serious compliance with a program of risk reduction must be urgently considered. Hoeg has described the mosaic of risk factors beyond the conventional and often ignored basic ones (JAMA, 1997, 277, 1387-1390). He provides thoughtful hope and encouragement for both patient and physician to do more in prevention of the subsequent predictable progression. We should look on a troponin positive vague unstable angina event as similar to a tremor which preceeds a subsequent earthquake. Although the mass of myocardium lost in such an episode may be small, it is a warning of the major acute myocardial infarction which can be predicted to follow at a later time if the course of the individual patient is not altered. Troponin is the objective evidence.

Cardiac troponin I measurement with the ACCESS immunoassay system: analytical and clinical performance characteristics.

We evaluated the ACCESS cardiac troponin I (cTnI) immunoassay as a marker for myocardial infarction (MI). Total imprecision was 6.0% to 13.5%, the minimum detectable concentration was 0.007 microg/L, and the limit of quantitation was 0.046 microg/L. Comparison of cTnI measurement between the ACCESS and Stratus systems (n = 114) showed a proportional difference: ACCESS cTnI = 0.0996 Stratus cTnI + 0.049 microg/L (r = 0.811). Fifty-nine of 61 ambulatory patients without cardiac symptoms had no detectable cTnI (95% range, 0.00 to 0.025 microg/L). The optimum cutoff for discriminating MI (n = 289, 45 with MI) was 0.15 microg/L by receiver operator characteristic curve analysis; at this cutoff, the ACCESS cTnI assay showed a sensitivity of 88.9% (95% CI, 79.7-98.1%) and specificity of 91.8% (95% CI, 88.4-95.2%). The ACCESS cTnI assay results showed 89.4% and 93.0% concordance with the MB isoenzyme of creatine kinase (CK-MB) mass and Stratus cTnI results, respectively, for classification of patients with suspected MI. The ACCESS cTnI assay appears to show sensitivity and specificity comparable with those of both CK-MB mass and Stratus cTnI assays for the diagnosis of MI in patients presenting within 12 h of onset of symptoms.

The cardiac profile and proposed practice guideline for acute ischemic heart disease.

Presented with an ever-increasing array of potential tests of myocardial injury, the clinical pathologist in conjunction with physicians in primary care, cardiology, and other clinical disciplines must evolve a practical approach for each individual institution. This involves identifying the tests available for immediate (stat) or timed performance, the appropriate patients for whom testing is desired, the schedule of frequency and duration of testing, and the manner in which the test results are to be interpreted. A guideline is presented to address these issues with the purpose of stimulating local adoption of an appropriately modified version to accommodate the current state of the art. Selective choice of an early marker, creatine kinase MB by mass immunoassay, in conjunction with cardiac troponin I (cTnI), is proposed as the appropriate combination of laboratory tests that emphasizes the cardiospecificity of cTnI for the variety of applications in which the "cardiac profile" formerly has been used, including the spectrum of clinical settings in which suspected myocardial infarction must be considered. A rationale is provided with emphasis on the relative merit of the various biochemical markers in contrast with other modalities for evaluating suspected myocardial injury.

Why cardiospecificity is preeminent in myocardial markers of injury.

The most critical facet of a biochemical marker of ischemic heart disease is cardiospecificity. This flows from the fact that symptoms and alternative objective studies including coronary arteriography and electrocardiography are frequently insensitive in detecting coronary artery disease. The timely appearance of biochemical evidence of myocyte necrosis firmly asserts the presence of life threatening multi-focal coronary atherosclerosis which is often not otherwise knowable. Compliance in the response of physician and patient clearly depend on the perception of persuasive biochemical testimony.

Comparison of cardiac troponin I and lactate dehydrogenase isoenzymes for the late diagnosis of myocardial injury.

Cardiac troponin I (cTnI) is a highly specific marker that is elevated in the blood for several days following myocardial infarction. The lactate dehydrogenase (LD) isoenzyme 1 to isoenzyme 2 ratio (LD1/LD2) is the established marker for the late diagnosis of myocardial infarction. In this study, the sensitivity of cardiac troponin I (cTnI) and LD1/LD2 were compared as late markers of myocardial injury over a 5-day period in 36 patients admitted with a diagnosis of myocardial infarction to the coronary care unit. Over this period, the sensitivity of cTnI was significantly greater than that of LD1/LD2 (P < .05). The concurrent elevation of both cardiac markers of the five day period range from 53.1% to 79.4%. However, this low concordance was largely due to an LD1/LD2 < 1 in the presence of an increased cTnI. The average discordance over the 5-day period was 29.5%. Because cardiac troponin I (cTnI) has greater sensitivity than lactate dehydrogenase isoenzymes for delayed diagnosis of myocardial injury and is a more cost-effective test, the authors recommend it as a test of choice in this setting.

Effects of cocaine on anterior pituitary and gonadal hormones.

Acute and chronic cocaine administration has been reported to change endocrine and neurochemical functions in animals and human drug abusers. This study examined the effects of acute cocaine administration on anterior pituitary and gonadal hormones in male human volunteers without a history of drug abuse. Using a double-blind, randomized study design, luteinizing hormone, follicle-stimulating hormone (FSH), prolactin and testosterone levels were measured in 12 healthy men before and after intranasal administration of 2 mg/kg cocaine or placebo. Each subject was studied twice, serving as his own control. Compared to placebo, both luteinizing hormone, and, to a lesser degree, follicle-stimulating hormone levels increased significantly after cocaine, reaching a peak value 60 min after the administration of the study drug. This pattern is consistent with a possible cocaine induced rise in gonadotropin-releasing hormone and subsequent rise in luteinizing hormone and follicle-stimulating hormone due to stimulation of gonadotroph cells in the pituitary gland. Neither cocaine nor placebo induced a change in testosterone levels. Prolactin levels showed a decrease from base line after both placebo and cocaine administration, with a significantly more pronounced decrease after cocaine. This likely reflects the combination of the physiologic diurnal variation in prolactin secretion and an added inhibitory effect on prolactin due to cocaine. These findings show that the acute administration of cocaine significantly alters anterior pituitary hormonal release patterns.

Endocrinopathy and ectopic hormones in malignancy.

This article reports progress in the field of endocrinopathies and focuses on the molecular aspects of these diseases. Implications for genetics and metabolic study are presented. Although limitations of earlier approaches are confirmed, progress is noted, particularly with regard to the contribution of octreotide scintigraphy. Integrated with the evolving applications of molecular insights, significant clinical progress has been recorded.

Myocardial markers of injury. Evolution and insights.

Knowledge of the pathophysiology of ischemic heart disease has advanced in parallel with awareness of the significant limitations inherent in clinical assessment. Biochemical assays, long established as the most reliable means of detecting myocardial injury, have improved significantly. Creatine kinase MB, now optimally measured by the newer mass monoclonal antibody assays, and also measurement of the cardiac troponins objectively identify adverse prognosis. Cardiac troponin I appears to have significant advantages over other markers and may become the assay of choice. This is attributable to the confirmation of cardiospecificity claims regarding this marker. These assays permit increased appreciation of the continuous spectrum of ischemic myocardial injury, earlier diagnosis, refinement of the clinical assessment of risk, and evaluation of alternative treatment regimens. Reassessment of the incorporation of biochemical indicators for thrombolytic therapy can be anticipated. This paper integrates the clinical and biochemical literature in reviewing these concepts.

Preanalytical considerations in testing thyroid function.

Remarkable technical advances have permitted analytical measurement of thyrotropin (TSH) and estimates of free thyroxine (FT4) with precision, accuracy, and favorable economics. Combined with an increased appreciation of the key insights into the pituitary-thyroid relation, preanalytical considerations infrequently introduce confounding variables. In reviewing thyroid data, preanalytical considerations include physiological and specimen-based issues. Central to the improvement in thyroid assessment is the recognition that physiological individuals maintain their FT4 within narrow limits. When this deviates, there is a logarithmic response of the TSH concentration to the arithmetic shift in FT4. In effect, the TSH deviation magnifies the subtle shift in FT4. Artifact and other nonthyroid-related preanalytical considerations are infrequently the cause of nonconcordance when discrepancy occurs between the reported values for FT4 and TSH. When abnormalities of TSH and FT4 are encountered, the probability strongly favors a disease state rather than a preanalytical variable. Infrequent but real extrathyroidal pathophysiological states are increasingly recognized as a result of the reliable assessment of the pituitary-thyroid relation.

Economic considerations of point-of-care testing.

Point-of-care testing is a rapidly expanding trend. This review discusses some of the issues driving the development of this new approach to laboratory testing, assesses the factors appropriate in introducing and managing point-of-care testing, and directs attention to realistically assessing the potential for cost-effectiveness analysis. Although considered optimal, formal cost-effective analysis is limited. A commentary on the published literature of the field is presented. Observations are offered on the inadequacies of published studies that purport to describe this application. As an alternative, a more general assessment of the economic effect of point-of-care testing in the general context of the laboratory mission is recommended. Suggested guidelines are included.

Effects of cocaine on cortisol secretion in humans.

The effects of acute cocaine administration on the pituitary adrenal axis in humans without a history of drug abuse are unknown. The authors studied 12 male volunteers twice in a double-blinded, placebo-controlled, randomized fashion. After intranasal administration of 2 mg/kg cocaine, cortisol levels were significantly higher than after placebo administration. The authors concluded that acute administration of cocaine to humans increases cortisol secretion.