Volume 33, Issue 2

Based on the original recommendation of the Expert Panel on the Theory of Reference Values of the International Federation of Clinical Chemistry (IFCC) dating back to the 1980s, updated guidelines were recently published under the auspices of the IFCC and the Clinical Laboratory Standard Institute (CLSI). Whereas the theory and the fundamentals of the reference value concept (definition, selection of reference individuals, preanalytical and analytical requirements, analysis of reference values) have not been modified, the updated guidelines add valuable improvements (transference, validation and verifying reference intervals). However, certain limitations remain which will be discussed in the present article. Zusammenfassung Die ursprünglichen Empfehlungen des Expert Panel on the Theory of Reference Values der International Federation of Clinical Chemistry (IFCC) datieren aus den 1980er-Jahren. Auf der Grundlage dieser Empfehlungen wurden kürzlich überarbeitete Empfehlungen unter der Schirmherrschaft der IFCC und des Clinical Laboratory Standard Institute (CLSI) herausgegeben. Die Theorie und die Konzepte der Referenzwerte (Definition, Auswahl der Referenzindividuen, präanalytische und analytische Anforderungen, statistische Analyse der Referenzwerte) wurden nicht verändert. Dagegen bringen die geänderten Empfehlungen deutliche Verbesserungen (Transferierbarkeit, Bestätigung der Referenzbereiche). Dennoch, verbleiben einige Problemfelder, die in diesem Artikel ebenfalls diskutiert werden.

Background : The current dogma of establishing intra-laboratory reference limits (RLs) and their periodical reviewing cannot be fulfilled by most laboratories due to the expenses involved. Thus, most laboratories adopt RLs from external sources often neglecting the problems of transferability. Presently accepted validation concepts still require experimental expenses. Several attempts were undertaken to derive RLs from the large data pools stored in modern laboratory information systems. Former indirect procedures were not generally accepted, but were recently further developed and combined with direct exclusion criteria and applied to estimate RLs of the catalytic activity concentrations of enzymes. This approach was now applied to several electrolytes in serum and plasma most commonly applied in clinical chemistry. Methods : A smoothed kernel density function was estimated for the distribution of the mixed data of the sample group (combined data of non-diseased and diseased subjects). It was assumed that the “central” part of the distribution of all data represents the non-diseased (“healthy”) population (non-pathological values) with high probability. The central part was defined by truncation points using an optimisation method, and was used to estimate a Gaussian distribution of the values of non-diseased subjects. This distribution was now considered as the distribution of the non-diseased subgroup. The percentiles of this parametrical distribution were calculated to obtain unimodal reference intervals. Results : The RLs obtained from different laboratories were similar to recently published values established by direct procedures. Stratification for gender was not necessary, but in some cases for age. With rising age, an increase of the upper RL and of the reference range was observed for potassium. Hospitalisation affected the RLs of sodium, potassium, calcium and magnesium, but not of phosphate. In the case of sodium, the data of at least five regional laboratories could be combined to common RLs. The presented indirect procedure was further validated with a large dataset of potassium concentrations from the NHANES III study with five groups of different health status. Conclusions : The proposed strategy of combining exclusion criteria with an indirect method led to RLs from intra-laboratory data pools for electrolytes which were plausible in comparison to published data obtained by the generally accepted direct approach. The combined concept, however, still requires further investigations. Therefore, it is presently only recommended for checking and reviewing already existing RLs. Zusammenfassung Hintergrund : Das derzeitige Dogma zur Erstellung von intra-laboratoriellen Referenzgrenzen (RLs) und deren periodische Überprüfung kann von den meisten Laboratorien wegen des hohen Aufwandes nicht erfüllt werden. Daher übernehmen die meisten Laboratorien RLs von externen Quellen und vernachlässigen dabei meistens die Transferproblematik. Aktuelle Validierungskonzepte erfordern ebenfalls noch einen hohen Aufwand. Verschiedene Versuche wurden daher unternommen, RLs aus den großen Datenpools moderner Datenverarbeitungssysteme abzuleiten. Diese indirekten Verfahren haben sich aber bisher zunächst nicht allgemein durchgesetzt. Sie wurden aber kürzlich weiterentwickelt und mit direkten Ausschlusskriterien kombiniert. Nachdem dieses Konzept auf die Bestimmung von RLs (nicht normalverteilter) katalytischer Enzymaktivitätskonzentrationen beschrieben wurde, wurde es jetzt auf normalverteilte Elektrolytkonzentrationen angewendet. Methodik : Eine geglättete Kernel Dichtefunktion wurde für die Verteilung von gemischten Daten (von kranken und nicht-kranken Personen) angewendet. Dabei wurde angenommen, dass der „zentrale“ Teil der Verteilung aller Daten überwiegend die nicht-kranke („gesunde“) Subpopulation repräsentiert. Der zentrale Teil wurde durch Trunkierungspunkte mittels einer Optimierungsmethode definiert. Dieser Teil diente zur Schätzung der Gauss-Verteilung der nicht pathologischen Werte. Die Perzentilen dieser Verteilung ergaben die Referenzintervalle. Ergebnisse : Die von acht Laboratorien geschätzten RLs stimmten gut mit Literaturangaben, die mit der klassischen direkten Methode bestimmt wurden, überein. Stratifizierung nach Geschlecht war nicht erforderlich, wohl aber in einigen Fällen nach dem Alter. Insbesondere stiegen die oberen RLs bei Kalium mit dem Alter an. Hospitalisierung beeinflusste die RLs bei allen Elektrolyten mit Ausnahme von Phosphat. Die RLs für Natrium konnten bei fünf Laboratorien zu gemeinsamen RLs kombiniert werden. Das vorgestellte indirekte Verfahren wurde zusätzlich mittels eines großen Datensatzes für Kalium aus der NHANES-III-Studie mit fünf Gruppen unterschiedlichen Gesundheitsstatus validiert. Schlussfolgerung : Die vorgeschlagene Strategie eines weiterentwickelten indirekten Verfahrens mit direkten Ausschlusskriterien führte zu plausiblen RLs bei den untersuchten Elektrolyten. Dieses Konzept bedarf jedoch noch weiterer Untersuchungen bevor es allgemein empfohlen werden kann. Daher wird es vorerst nur zur Überprüfung von bestehenden RLs vorgeschlagen.

The German guidelines for early detection of prostate cancer propose the use of digital rectal palpation and prostate specific antigen (PSA). PSA levels above 4 μg/L are considered to be suspect. However, method comparison of six different assays resulted in differences up to 20% in the range of 4 μg/L, although all assays used the Stanford 90/10 (WHO 96/670) calibration. Interpretation of PSA levels therefore has to take into consideration assay-specific characteristics, using assay-specific local reference ranges. However, the estimation of reference ranges by, e.g., analysis of frequency distribution failed with regard to the high prevalence of benign prostate hyperplasia. PSA velocity is proposed for early detection. Interpretation of PSA velocity especially at low PSA levels has to take into consideration analytical imprecision and biological variation.

The German guidelines for early detection of prostate cancer propose the use of digital rectal palpation and prostate specific antigen (PSA). PSA levels above 4 μg/L are considered to be suspect. However, method comparison of six different assays resulted in differences up to 20% in the range of 4 μg/L, although all assays used the Stanford 90/10 (WHO 96/670) calibration. Interpretation of PSA levels therefore has to take into consideration assay-specific characteristics, using assay-specific local reference ranges. However, the estimation of reference ranges by, e.g., analysis of frequency distribution failed with regard to the high prevalence of benign prostate hyperplasia. PSA velocity is proposed for early detection. Interpretation of PSA velocity especially at low PSA levels has to take into consideration analytical imprecision and biological variation.

Acute poisoning is a medical emergency situation and requires urgent but adequate medical intervention. The outcome depends on accurate primary care, the correct identification of poison(s) and adequate therapeutic decisions. The present paper reviews the literature concerning the role of analytical toxicology in emergency medicine with particular focus on the last few years. This study is mainly based on a PubMed search: “clinical toxicology review (urine, serum)”. Many acutely poisoned patients are treated with no laboratory support other than general clinical chemistry, haemostaseology and haematology. Emergency toxicological analyses that could influence immediate patient management, if offered on the basis of 24-h availability, are most often restricted to ethanol, oximetry and drugs of abuse in urine. Despite paracetamol (acetaminophen) being the top entry on all hit lists of poison control centres worldwide with few exceptions, the availability of its determination in blood on an urgent basis is not standard even at hospitals with large accident and emergency departments. Therefore, recommendations regarding the assays and methods that should be provided locally and at regional centres were provided for the US and UK, and should be adapted for Germany. Emergency toxicological analyses that could influence immediate patient management are relatively few in number and are remarkably similar worldwide. Recommendations for the US and UK are compared in the present paper together with suggestions for Germany. The first group of these assays should be provided locally by larger hospitals with emergency and intensive care units with a turnaround time (TAT) of less than 1 h. Other assays (second group) and a systematic toxicological analysis that can help improve patient management after a period of primary stabilisation of vital functions and general supportive therapy can be provided from regional centres with a TAT of 4 h. The need for such centres and the repertoire of tests and methods that should be available will be adapted also and discussed. It is well known that comprehensive toxicological analysis incorporating various methods can identify much more substances than are clinically suspected. At the same time, this information might have no clinical utility owing to the time required for sampling, transportation, analysis and reporting, or because the toxicological report might be inconsequential. This has contributed to a range of clinical opinions and practices, from a minimalist approach to a “shotgun” approach of broad-based laboratory testing. The present review should help to understand and discuss the pros and cons of both approaches.

Acute poisoning is a medical emergency situation and requires urgent but adequate medical intervention. The outcome depends on accurate primary care, the correct identification of poison(s) and adequate therapeutic decisions. The present paper reviews the literature concerning the role of analytical toxicology in emergency medicine with particular focus on the last few years. This study is mainly based on a PubMed search: “clinical toxicology review (urine, serum)”. Many acutely poisoned patients are treated with no laboratory support other than general clinical chemistry, haemostaseology and haematology. Emergency toxicological analyses that could influence immediate patient management, if offered on the basis of 24-h availability, are most often restricted to ethanol, oximetry and drugs of abuse in urine. Despite paracetamol (acetaminophen) being the top entry on all hit lists of poison control centres worldwide with few exceptions, the availability of its determination in blood on an urgent basis is not standard even at hospitals with large accident and emergency departments. Therefore, recommendations regarding the assays and methods that should be provided locally and at regional centres were provided for the US and UK, and should be adapted for Germany. Emergency toxicological analyses that could influence immediate patient management are relatively few in number and are remarkably similar worldwide. Recommendations for the US and UK are compared in the present paper together with suggestions for Germany. The first group of these assays should be provided locally by larger hospitals with emergency and intensive care units with a turnaround time (TAT) of <1 h. Other assays (second group) and a systematic toxicological analysis that can help improve patient management after a period of primary stabilisation of vital functions and general supportive therapy can be provided from regional centres with a TAT of 4 h. The need for such centres and the repertoire of tests and methods that should be available will be adapted and discussed. It is well known that comprehensive toxicological analysis incorporating various methods can identify much more substances than are clinically suspected. At the same time, this information might have no clinical utility owing to the time required for sampling, transportation, analysis and reporting, or because the toxicological report might be inconsequential. This has contributed to a range of clinical opinions and practices, from a minimalist approach to a “shotgun” approach of broad-based laboratory testing. The present review should help to understand and discuss the pros and cons of both approaches.

Mycophenolate mofetil (MMF, CellCept ® , Roche Pharmaceuticals) received its first approval for the prevention of renal allograft rejection in 1995 and has now become the most frequently used antiproliferative agent in maintenance immunosuppressive therapy for kidney, pancreas, liver, and heart transplantation. In 2004, a second mycophenolate formulation – the enteric-coated mycophenolate sodium (EC-MPS, Myfortic ® , Novartis Pharma) – was introduced. Whereas therapeutic drug monitoring (TDM) is well established for other immunosuppressants, the use of this tool for individualization and optimization of mycophenolate therapy remains a matter of debate during these years. This article focuses on the basic pharmacology of mycophenolic acid and current knowledge about the utility of monitoring mycophenolic acid concentrations. Different tools for performing TDM of mycophenolic acid, current recommendations for TDM of MMF in transplantation medicine, as well as analytical techniques available will be discussed. Zusammenfassung Mycophenolat Mofetil (MMF, CellCept ® , Roche Pharma) wurde zur Prävention der akuten Abstoßung bei Nierentransplantation im Jahr 1995 zugelassen und ist heute die am häufigsten verwendete antiproliferative Substanz in der immunsupressiven Erhaltungstherapie der Nieren-, Pankreas-, Leber- und Herztransplantation. Im Jahr 2004 wurde ein Natriumsalz der Mycophenolsäure (MPA) – enteric coated mycophenolate sodium (EC-MPS, Myfortic ® , Novartis Pharma) – eingeführt. Während ein Therapeutisches Drug Monitoring (TDM) für andere Immunsuppressiva gut etabliert ist, wird die Verwendung dieses Instruments zur Individualisierung und Optimierung der Mycophenolsäuretherapie seit Jahren kontrovers diskutiert. Diese Zusammenfassung konzentriert sich auf die zugrunde liegende Pharmakologie von MPA und auf den derzeit gültigen Kenntnisstand hinsichtlich des Nutzens einer Bestimmung der MPA-Konzentration im Blut. Es werden die verschiedenen Ansätze für das TDM von MPA, die aktuellen Empfehlungen für das Monitoring der Therapie mit MMF in der Transplantationsmedizin sowie die verfügbaren analytischen Techniken diskutiert.

In addition to the monographs which have been published recently by the working group “Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [1–3], new monographs have been written. The aim of these monographs is to provide an overview on the information which is important for the request and interpretation of the results. Therefore, the targeted readers are laboratory health professionals and the receivers of the reports. In this series, several antidepressant and antipsychotic drugs are presented. It is worth noting that the monograph on the antipsychotic clozapine has already been published in 2005 [1]. Information on the indications for therapeutic drug monitoring (TDM), protein binding, metabolic pathways and enzymes involved, elimination half-life time and elimination route(s) of the parent drug and therapeutic or toxic concentrations is provided. Because pre-analytical considerations are of particular importance for therapeutic drug monitoring, information regarding the optimal point in time for the determination of drug concentrations and achievement of steady-state concentrations after changing the dose is given. Furthermore, the stability of the drug and its metabolite(s) after blood sampling is described. For readers with a specific interest, references to important publications are provided. The number of the monographs will be continuously increased. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to comments by the readers. Zusammenfassung In Ergänzung zu den in den letzten vier Jahren publizierten Arzneimittelmonographien der Arbeitsgruppe Medikamente der Schweizerischen Gesellschaft für Klinische Chemie (SGKC) [1–3], sind nun weitere Monographien erstellt worden. Ziel dieser Monographien ist es, dem Labormediziner bzw. dem Empfänger der Befunde eine Übersicht über die wichtigsten Informationen zu geben, die für die Veranlassung einer Analyse bzw. für die Interpretation der Resultate hilfreich sind. In dieser Serie werden eine große Zahl von Antidepressiva und Antipsychotika präsentiert. Es muss noch darauf hingewiesen werden, dass die Monographie zu Clozapin, Neuroleptikum, bereits 2005 publiziert worden ist [1]. In den einzelnen Monographien werden klinisch pharmakologische Angaben wie zum Beispiel Indikation für das Therapeutic Drug Monitoring, Proteinbindungen, Metabolisierungswege und daran beteiligte Enzyme, Halbwertzeiten und Eliminationswege der Muttersubstanz, sowie Informationen zu therapeutischen bzw. toxischen Bereichen, zur Verfügung gestellt. Da die Präanalytik gerade beim Therapeutic Drug Monitoring eine wichtige Rolle spielt, werden auch hier Angaben gemacht zu welchem Zeitpunkt eine Bestimmung der Arzneimittelkonzentration sinnvoll ist und wann, nach einer Dosisänderung, der steady-state erreicht ist. Außerdem werden Angaben über die Stabilität der Medikamente bzw. ihrer Metaboliten nach der Blutentnahme gemacht. Für die interessierten Leser sind die verwendeten Referenzen als Zitate aufgeführt. Die Zahl der Monographien wird fortlaufend ergänzt. Die aktuellsten Versionen der Monographien sind auf der Homepage der SGKC abrufbar (www.sscc.ch). Wir hoffen, dass diese Monographien im Umgang mit dem Therapeutic Drug Monitoring hilfreich sein werden und freuen uns über Kommentare und Bemerkungen.

The desired properties of an ideal anticoagulant should be reliable action, a defined, selective mode of action, a wide therapeutic window, and predictable pharmacokinetics. Numerous new substances were developed as a substitute for oral anticoagulants and heparins. Owing to their superiority in clinical studies, some of these drugs have already been approved. The hemostaseological laboratory is now challenged to detect a sufficient anticoagulation while avoiding bleeding by overdosing. The purpose of this review is to describe novel anticoagulants in current use and the possible tests for drug monitoring in heparin-induced thrombocytopenia and in the perioperative prevention of thromboses. Zusammenfassung Ziel eines idealen Antikoagulanz ist eine zuverlässige Wirkung, ein definierter selektiver Wirkungsmechanismus, eine große therapeutische Breite und eine vorhersagbare Pharmakokinetik. Als Ersatz für die oralen Antikoagulantien und Heparine wurden verschiedene neue Substanzen entwickelt, und aufgrund ihrer Überlegenheit in klinischen Studien teilweise bereits zugelassen. Das hämostaseologische Labor ist nun gefordert, eine ausreichende Antikoagulation festzustellen bzw. Überdosierungen zu erkennen. In diesem Review werden die neuen Antikoagulantien zur Therapie der Heparin-induzierten Thrombozytopenie (HIT2) und zur perioperativen Thromboseprophylaxe sowie die Möglichkeiten eines Dosismonitorings vorgestellt.

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