External quality assessment of laboratory performance in analysis of toxicological cases.

A mean of 44 members of the United Kingdom national external quality assessment scheme (UKNEQAS) for toxicology reported analytical findings on 10 toxicological cases circulated between December 1995 and February 2000. Material distributed usually consisted of a 5ml blood and a 20ml urine sample simulated by quantitative addition of drugs and their metabolites to material donated by volunteers and patients. The samples were accompanied by a brief outline of the circumstances surrounding the case. Laboratories were requested to report their analytical findings, list methods of analysis, and provide interpretation of their findings. The mean overall success rate for identification of drugs or their pharmacological group was 76%, failure being largely by laboratories providing an immunoassay-based screening service for a fixed range of drug groups. The latter laboratories indicated that cases would be referred to regional toxicology centres for further investigation or confirmation. The coefficient of variation of measurements was <7% for routine analytes, such as ethanol and paracetamol, but 26-44% for tricyclics and opiates. There were 3% false positive reports. The quantity and content of interpretative comment provided by the laboratories was very variable. A number provide nothing in addition to the analytical result.

A survey of extraction techniques for drugs of abuse in urine.

Sixty nine participants in the United Kingdom national external quality assessment scheme for drugs of abuse in urine reported details of their sample extraction technique by questionnaire. Laboratories were categorised by differences in technique and their analytical test results compared for samples containing D-amfetamine 0.4 (4) and 0.8 (3) mg/l, morphine 0.4 (4) and 0.8 (4)mg/l, and benzoylecgonine 0.15/0.2 (2) and 0.45/0.5 (4) mg/l. Values in parentheses are numbers of samples. For amfetamine, there was no significant difference in the frequency of true positive results between liquid-liquid or solid phase extraction and the Toxi-Lab A system at 0.8 mg/l. Toxi-Lab A gave significantly fewer positives when operating below its specified threshold at 0.4 mg/l. Paradoxically, laboratories using >5 ml urine volume performed less well. Acidification of the extract before volume reduction gave significantly more true positives. For extraction of morphine, solid phase systems significantly outperformed both liquid-liquid and the Toxi-Lab A system at both 0.8 and 0.4 mg/l. No significant differences between extraction techniques were demonstrated for analysis of benzoylecgonine.

An audit of therapeutic drug monitoring service provision by laboratories participating in an external quality assessment scheme.

Therapeutic drug monitoring services were investigated in a questionnaire sent to all subscribers to the United Kingdom National External Quality Assessment Scheme for Therapeutic Drug Assays. Questions were posed on assay availability and use, target ranges, and reporting procedures for digoxin, lithium, phenytoin, phenobarbitone, carbamazepine, theophylline, and valproic acid. One hundred fifty-seven laboratories replied and, except for lithium, 45% reported in mass units, 34% in molar units, and 22% a mixture of mass and molar units. Target ranges for lithium, digoxin, carbamazepine, and phenobarbitone were highly variable but ranges for phenytoin, theophylline, and valproic acid were more consistent. Immunoassay was the most popular methodology although high-performance liquid chromatography was commonly used for anticonvulsants. Paper copies of results were provided by 93% of laboratories, 40% reported by telephone, 12% by fax, and 28% by computer. Additional data, mainly dose, time of last dose, and duration of therapy were requested by 55% to 67% of laboratories. Grades of staff authorizing results ranged from nurses to senior consultants, and collaboration with pharmacists occurred in 26% of laboratories. Most laboratories provided a daily analytical service and 73% offered a 24-hour emergency service. This audit unexpectedly identified use of a wide range of target concentrations, particularly for digoxin and lithium.

External quality assessment of techniques for the detection of drugs of abuse in urine.

Five chromatographic and six immunoassay techniques were compared using data reported by 131 participants in the UK National External Quality Assessment Scheme for Drugs of Abuse in Urine. Twenty five samples were studied containing none or one of three concentrations of amphetamine, barbiturates, benzodiazepines, benzoylecgonine, methadone and morphine. Technique sensitivity and specificity achieved with realistic clinical samples of 25 mL vol were assessed as the percentage of true positive and true negative tests, respectively. Thin-layer chromatography was inadequate for the detection of several analytes, the sensitivity for 0.5 mg/L of benzoylecgonine being < 30%, and for 1.5 mg/L of amphetamine < 86%. Gas chromatography with mass spectrometry was significantly less sensitive than other techniques for the detection of 0.5 mg/L of benzoylecgonine (71%) and 1.5 mg/L of morphine (88%). High-performance liquid chromatography was the most sensitive for amphetamine. Immunoassays performed well when operating above their specified cut-off concentrations but, because they are directed to quinalbarbitone showed reduced cross-reactivity with amylobarbitone, the barbiturate more commonly prescribed in the UK.

An exceptional case of lethal disulfiram-alcohol reaction.

A case of fatal disulfiram-alcohol reaction due to ingestion of ethanol and antabuse is presented. Unusual autopsy findings and toxicological results are described. This case represents a report of corrosion lesion in the lower oesophagus and stomach due to a violent chemical reaction in situ and also the highest blood concentration of acetaldehyde (41 mg/l) ever recorded.

Performance of techniques used to detect drugs of abuse in urine: study based on external quality assessment.

Twenty-five samples of lyophilized urine from the U.K. External Quality Assessment Scheme for Drugs of Abuse were analyzed by an average of 95 laboratories between April 1987 and December 1989. Samples contained mixtures of analytes and included replicated concentrations of morphine, methadone, amphetamine, and cocaine at 0, 1, 2, and 5 mg/L and of benzoylecgonine at 0, 0.4, 1, 2, and 4 mg/L. Some chromatographic techniques were inadequate for detecting morphine, amphetamine, cocaine, and benzoylecgonine at the lower concentrations of analytes studied: gas-liquid chromatography was least sensitive for morphine; in-house thin-layer chromatography (TLC) was least sensitive for the other analytes. Few significant differences in specificity were detected between techniques, although significant interference from structurally related compounds was demonstrated in assays of morphine, methadone, and amphetamine. Exceptions were the Boehringer (BCL) test for opiates and TLC applied to amphetamine and benzoylecgonine, which demonstrated considerable lack of specificity.

A survey of drugs of abuse testing by clinical laboratories in the United Kingdom. Steering Committee for the UK-External Quality Assessment Scheme for Therapeutic Drug Assays.

An external quality assessment survey of testing facilities in UK clinical laboratories for the detection of drugs of abuse was made with nine freeze-dried samples of urine containing representative drugs with their metabolites from the following seven classes; amphetamines and stimulants, barbiturates, cannabinoids, cocaine, minor tranquillisers, opiates and non-opiate narcotics. Reports were received from 120 laboratories. Thirty six per cent of laboratories reported on all seven drug classes and 71% on the five classes excluding cannabinoids and cocaine. A single drug screening technique was used by 32% of laboratories whilst 46% were able to perform tests by both immunological and chromatographic techniques. There was a mean level of false positive reporting of 4.3% and an observed level of false negative reports of 8.4%, the latter underestimating the true frequency. The minor tranquillisers, cocaine and benzoyl ecgonine were the most frequently missed analytes. Several false reports had important potential implications for patient care.

Fatal phenolphthalein poisoning with fulminant hepatic failure and disseminated intravascular coagulation.

A 32-year-old female ingested an unknown quantity of Nylax tablets containing phenolphthalein. This results in widespread organ involvement, predominantly causing liver damage and disseminated intravascular coagulation. The eventual cause of death was massive liver necrosis. We suggest that phenolphthalein was responsible for the widespread damage.

Tentative identification of a digoxin-like immunoreactive substance.

Three independent immunoassays gave significantly different results when digoxin concentrations were measured in plasma samples from a 68-year-old male patient with renal and liver impairment. These differences were used to provide a means of isolating a digoxin-like immunoreactive substance (DLIS) by high-pressure liquid chromatography. Examination of this fraction by fast atom bombardment-mass spectrometry provided data to support the hypothesis that excess bile acids might be the source of the DLIS in our patient which may also explain the DLIS observed in neonates.

Urinary oxalate levels are not affected by dietary purine intake or allopurinol.

We showed previously that ingestion of a non-specific high purine diet by healthy subjects increased not only urinary uric acid levels but urinary oxalate as well. Both increments were reduced significantly during concomitant allopurinol therapy. The present study was undertaken to investigate these findings in more detail under carefully controlled dietary conditions where a single specific purine, guanosine, was used as an additive and several different methods for oxalate determination (GLC, HPLC, isotacophoresis) were compared with the enzymatic method used previously. Results obtained by two direct techniques of oxalate determination showed no significant alteration in oxalate levels during any dietary regime, suggesting that the earlier results derived from problems inherent in the experimental design and methodology employed. The study confirmed that one of the beneficial effects of allopurinol was to reduce dietary purine absorption. The results may thus provide a logical explanation for the reduced incidence of urolithiasis during allopurinol therapy in some idiopathic oxalate stone formers addicted to purine-rich foods and beverages.