Absorption of doxorubicin hydrochloride during bladder washings in treatment of noninvasive bladder tumors.

The absorption of doxorubicin hydrochloride (Adriamycin) in or through the urothelium has been determined as the difference between the instilled amount and the amount recovered after complete drainage of the bladder in 9 patients suffering from superficial urinary bladder tumors (grade I-II). A total of 22 absorption experiments were done. The relative deficit was found to be between 0 and 16 per cent (median 4 per cent). One of the reasons for the variations in the relative deficit was probably intravesical bleedings. One hundred seventy-two mumol. (100 mg.) doxorubicin was dissolved in 100 ml. isotonic saline, and the instilled liquid was retained in the bladder for one hour. No patient showed any sign of systemic side effects caused by doxorubicin. The results seem to indicate that it is possible to use a dose for intravesical instillation which is five times as high as the maximum dose for intravenous administration.

Strategies and methods for the analytical investigation of urinary calculi.

Methods for the investigation of urinary calculi are briefly reviewed. Infrared spectrometry and X-ray diffraction provide results on the actual salts, including the different degree of hydration, in contrast to wet chemistry which only measures the ions of salts. Most often the quantitated ions can, however, be combined into salts by calculation, but the different degree of hydration cannot easily be recorded by wet chemistry. Wet chemistry, infrared spectrometry and X-ray diffraction can all provide reliable results. Routine performance should be generally improved by providing quantitative instead of 'qualitative' results. In wet chemistry calculation of recovery should be obligatory. Spectra covering 4000-400 cm-1 and probably also objective evaluation are important fields for improving infrared spectrometry. A laboratory service based on X-ray diffraction or infrared spectrometry should be available for laboratories using wet chemistry to investigate rare calculi. The results should preferably be given in molar units in accordance with IFCC recommendations. Names of components should conform to the IUPAC-nomenclature and trivial names should be avoided.

Prothrombin time standardization and temperature problems.

The reaction temperature is crucial for enzymatic reactions. Difficulties in controlling the temperature in the tilt test tube technique for the prothrombin time test are illustrated. An improved detailed description of the technique is suggested for standardization purposes. Mixing of the specimen with the reagent should be done in the water bath. The test tubes should be immersed deeply into the bath. Recording of the temperature in the reaction mixture is recommended. When using plastic test tubes the temperature problems may be greater than with glass test tubes. Some heat denaturation of coagulation enzymes may take place at 37 degrees C. Lowering the temperature of the reaction to 30 degrees C and perhaps photometric recording of the coagulation should be included in a suggested future optimized reference method.

Inter-laboratory comparison of acid-base variable in human blood and in quality control materials.

Routine results, pH, partial pressure of carbon dioxide (pCO2) and of oxygen (pO2), and standard hydrogen carbonate ion concentration (SBC) in identical specimens of arterial blood from patients deviate substantially. The results from seven laboratories (each laboratory examining the same 12 patients and the same five types of quality control materials) and evaluation in terms of accuracy and precision suggest the variations between days (delta 2) and single measurements (sigma 2) to be the main factors for these deviations. A reduction of these variations must have the highest priority in quality control programmes, since the variations mask possible true level deviations between laboratories. The five control materials (Qualicheck, Quantra whole blood level I-II-III and hemolyzed donor blood) are not fully optimal as substitutes for patient blood in such quality control programmes.

Reduction of analytical error in measurement of the concentration of coagulation factors in plasma.

A modification of the method of Owren & Aas for the determination of relative arbitrary substance concentration of coagulation factors (II+VII+X) in plasma is presented. The coefficient of variation on repetends (today-yesterday) is reduced to 0.03 for results in the therapeutic as well as the 'normal' interval. An unusual composition of the plasma may be revealed. Thromboplastin-absorbed bovine plasma should be kept at -70 °C.

Mathematical expressions of measuring curves for concentration of clotting factors.

Conversion of coagulation time (t) to relative arbitrary substance concentration of coagulation factors (II + VII + X) abbreviated c(ra)) was originally made from a measuring curve corresponding to the equation log t = a(o) +a1 log c(ra). Three more suitable equations are presented and tested for fit: t = A(o) + A1 c(ra); t = B(o) + B1 c(ra) + B2 c²ra; log t = b(o) + b1 log c(ra) + b2 log c(ra)². Their suitability for the Simplastin®-A and Thrombotest® methods is also investigated. The last equation yields the best fit and replaces the error-prone reading of log-log curves by a calculation suitable for routine use.

The basis for common reference intervals for serum potassium.

In order to investigate the relevance of the currently used lower reference limit for S-Potassium in Danish hospital laboratories, analytical bias in the measurement of S-Potassium was compared with the lower reference limit in each of 52 Danish hospital laboratories. The acceptable bias range was estimated according to Gowans et al on the basis of the result of two different reference sample groups. The estimated acceptable 0.95 bias range was 0.24 mmol/L, so the observed bias range of 0.23 mmol/L was within this limit. As all preanalytical errors tend to increase the measured S-Potassium, all acceptable bias should be in the direction of decreasing the measured value. It can be concluded that analytical performance allows for more uniform (even common) reference interval(s) in all Danish and perhaps Nordic hospital laboratories, provided that preanalytical errors can be controlled.

A Nordic reference serum suitable for use as trueness control in the clinical routine laboratory.

The described reference serum is characterized by: liquid human serum at "normal" level stored in frozen state at -80 degrees C; minimum damage of proteins; aseptic preparation; cryoprecipitate and excess fibrin removed; serum cleared by ultracentrifugation; pH at 7.2-7.6; available in sealed glass ampoules with inert gas (one ml serum in each); specified components among most frequently analyzed analytes; homogeneity assured and stability monitored; produced under strict rules for good manufacturing practices (GMP). The assigned values are traceable to reference measurement procedures and reference materials of highest achievable metrological level; according to the present proposal the maximum allowable uncertainty of the assigned value is based on biological variation (shared common reference intervals); the uncertainty should ideally not exceed 1/5 of the maximum allowable bias of results obtained on patients samples (even 1/2 would theoretically be acceptable and, for a practical guide approximately < 1% may suffice). The present document provides some guidance of how the reference serum could be established in practice. The document also indicates the use of the material and further extension of the concept. The present work is done as a NORDKEM project.

Improvements in the routine investigation of urinary calculi.

Results from an external quality assessment program of urinary calculi analysis are shown. Some analytical improvements have been observed since a similar investigation two years earlier. Many erroneous results, however, were found. Best agreement was found between laboratories which produced results on an interval scale ("quantitative"). The laboratories in this group used either x-ray diffraction, infrared spectrometry, or wet chemistry. This, however, did not apply to the wet chemistry kit Merckognost 11003, which was used by 24 of the 57 participating laboratories. A study of this kit by our laboratory led to several improvements including better calibration and reduced imprecision. General recommendations of how to present the analytical results to the clinician are given.

Apparent interlaboratory variation using different types of reference sera.

Nine reference sera have been investigated in the same types of analyses in nine laboratories. Seven sera were of human origin, and two of animal origin. The analyses were repeated six times. Comparing the apparent interlaboratory variation of each reference serum, specimen associated effects were demonstrated. The effects were often considerable, and they were detected for nearly all of the analytes investigated: albumin, alkaline phosphatase, amylase, bilirubins, calcium (II), cholesterol, cobalamines, creatininium, creatine kinase, glucose, lactate dehydrogenase, magnesium (II), protein (total), and sodium ion. The effects are discussed according to their nature, viz. matrix effects, analyte simulation effects, and analyte concentration effects. These effects seemed distinct when poor methods were compared. Matrix effects were associated with lack of specificity, and analyte concentration effects with lack of linearity. The lyophilized serum from outdated bank blood showed the best agreement with fresh frozen pool of patients sera; the mixed bovine-equine lyophilized serum (AutonormTM, Nyegaard & Co. AS, Norway) showed the most frequent disagreements. Matrix and analyte simulation effects were probably the main cause.

Appropriate sera for calibration and control of specific protein assays.

An ultracentrifugation technique is described which makes it possible to prepare protein calibrators and control sera which (i) are stable (more than 8 years documented for nine proteins), (ii) are clear (remains clear for more than 8 years at -80 degrees C), (iii) contain genuine proteins (documented electrophoretically and immunologically), and (iv) are reproducible to prepare (collection and preparation).

Present analytical quality in the Nordic clinical chemistry laboratories.

An introductory review is given of the discussion in the Nordic countries on the definition, aim, and optimal organization of quality control. Published and unpublished Scandinavian works have been reviewed and commented under the following headlines: common chemical analyses, enzyme analyses, serum and plasma protein analyses, hormone analyses, drug analyses, hematological tests, and urine analyses. It is concluded that methods for calculating medical standards of analytical quality in clinical chemistry form the logical background for the design of an optimal quality control system, which will guarantee that analytical results well have a specified probability of satisfying the medical requirements.

Assessment of analytical quality in Nordic clinical chemistry laboratories using data from contemporary national programs.

The aim of this investigation was primarily to assess analytical quality expressed as between-laboratory, within-laboratory, and total imprecision, not in order to detect laboratories with poor performance, but in the positive sense to provide data for improving critical steps in analytical methodology. The aim was also to establish the present state of the art in comparison with earlier investigations to see if improvement in analytical quality could be observed.

A programme for assigning target values for external quality assessment schemes in countries with no authorized reference laboratories. Annex. Experiences with deviating results on Ektachem 700 XR.

The use of consensus values in external quality assessment schemes (EQAS) involves several problems and should preferably be replaced with target values obtained by methods of high metrological level. However, such values are difficult to obtain. In the present study we transferred values from the NIST (former NBS) certified reference serum SRM 909 to lyophilized and frozen test sera for various inorganic components using flame absorption or flame emission spectrometry. Enzyme values were assigned by laboratories of members of the former Scandinavian Enzyme Committee. The assignment was based on 2-4 determinations each day through 3 days of experiment. A total of 10 laboratories participated in the work. The results were utilized in a Danish EQAS. One practical concern is the fairly long time (9 months) which was needed for production, collection and compiling all data. To get an impression of how much dry chemistry analysers, e.g, could influence consensus values a Kodak Ektachem 700 XR was studied using lyophilized and frozen sera. The results are reported in the annex. On NIST SRM 909 the values found for sodium(I) were 6% too high even though the findings on frozen human sera were accurate. For aspartate aminotransferase a result three times the target values was found on a human lyophilized serum, while the values on the frozen sera only were slightly too high.

A quality manual for the clinical laboratory including the elements of a quality system. Proposed guidelines.

Development of quality manuals is a means for the promotion of quality in clinical laboratories by describing the total quality system. It also provides opportunity of checking whether the quality system is implemented in reality and demonstrates to the hospital administration and the clinicians that the laboratory is committed to quality. The intention of these guidelines is to describe the elements of the quality system for a large clinical laboratory, and to present such a system in the form of a quality manual. The proposed guidelines comply, where relevant, with ISO/IEC guide 25 'General requirements for the technical competence of testing laboratories' and EN 45001 'General criteria for the operation of testing laboratories'. The document may be used as an aid for laboratories wishing to be accredited according to EN 45001, or intending to apply for formal certification of their quality systems, according to ISO 9001 'Quality systems--Model for quality assurance in design/development, production, installation, and servicing' utilizing ISO 9004 'Quality management and quality system elements--guidelines; Part 2 Guidelines for service'. However, information about the minimum requirements for official recognition should be obtained from the particular accreditation or certification body concerned.

Practical aspects of internal quality assurance.

The final analytical quality of a result is influenced by external and internal factors. The quality of external elements is influenced by the individual laboratory through its choice of method and supply; such elements are, e.g. reference materials, calibrators, control materials, reagents, reagent kits, instruments and disposables. The internal elements can be described through rules for good laboratory practice (GLP), and include all aspects of internal quality assurance. In this paper, GLP is used to describe the proper milieau in which the optimally selected method is working. The control system for acceptance or rejection of any particular batch of analysis, as well as the long-term control, are also described separately.

[Quality assurance of results of clinical chemical analyses in Danish hospital laboratories]. / Kvalitetssikring af klinisk kemiske analyseresultater på danske hospitalslaboratorier.

During the past 35 years, voluntary professional assessment of quality of the results of analyses in Danish hospital laboratories has been undertaken under the auspices of the Danish Society of Clinical Chemistry. The analytical quality of the laboratories is described by their "imprecision" and "accuracy" as expressed by "coefficient of variation" and "bias", respectively. The participation in these programmes was 90%. During the period between 1968 and 1987, inter-laboratory variation decreased markedly where all analyses were concerned. To ensure the necessary and adequate quality, establishment of specifications of quality based on clinical/biological goals of quality has proved necessary. The commonest reasons for large imprecision and bias from the target values are less specific methods of analysis, errors in calibration and sporadic "outliers". As the result of a stable organisation for ensuring quality, Denmark is well equipped for the introduction of the great demands in documentation of quality which may be anticipated from the Common Market during the immediate future.