Stefanie Iwersen-Bergmann

Death after excessive propofol abuse

Abstract Abuse of the anaesthetic agent propofol (2,6-diisopropylphenol) is rare, but we report a case of a 26-year-old male nurse in which the autopsy showed unspecific signs of intoxication and criminological evidence pointed towards propofol abuse and/or overdose. Intravenously administered propofol is a fast and short-acting narcotic agent, therefore it seemed questionable whether the deceased would have been able to self-administer a lethal overdose before losing consciousness. The blood and brain concentrations corresponded to those found 1–2 min after bolus administration of a narcotic standard dose of 2.5 mg propofol/kg body weight. Extremely high propofol concentrations were found in the urine indicating excessive abuse before death. However, due to the short half-life of propofol, the cumulative effects of repeated injections should not be relevant for toxicity, since this would result in a blood level increase of only 1–2 μg/ml. Furthermore, the detection and quantitation of propofol in three different hair segments indicated chronic propofol abuse by the deceased. The results of the investigation suggest that death was not caused by a propofol overdose but by respiratory depression resulting from overly rapid injection.

Gamma-Hydroxybutyrate in Urine and Serum: Additional Data Supporting Current Cut-Off Recommendations

Besides the use of Gamma-Hydroxybutyrate (GHB) as a recreational drug, use of GHB as an agent in drug-facilitated crime should also be considered. In these cases, there is often a delay of several hours from the incident to collection of the samples. As GHB has a very short plasma half-life, the window of detection is small and in the majority of these specimens, levels of GHB are low. Because GHB is naturally occurring in humans, discrimination between endogenous and exogenous GHB is complicated, particularly in those samples with low concentrations. In this study, endogenous GHB levels of 50 serum and 50 urine samples were determined by GC-MS after conversion to trimethyl-silyl-derivatives. Concentrations in serum ranged from 0.62 to 3.24 mg/L (mean=1.14 mg/L; median=0.97 mg/L) and from 0.64 to 4.20mg/L (mean=1.21 mg/L; median=0.96 mg/L) in urine. Based on this substantial data, the current suggested lower cut-off of 4 mg/L in ante mortem serum samples could be confirmed. For urine, we propose the lower cut-off of 6 mg/L instead of 10mg/L to avoid false negative interpretation.

Fentanyl: Toxic or Therapeutic? Postmortem and Antemortem Blood Concentrations After Transdermal Fentanyl Application

In forensic toxicology, several fatal intoxications with fentanyl have occurred in the recent past, but there are rare discussions in the literature of postmortem fentanyl blood concentrations subsequent to lethal and non lethal applications. To study this problem, we analyzed postmortem blood concentrations (vena femoralis) of 118 cases with therapeutic use of fentanyl and compared them with serum levels of 27 living persons after therapeutic administration of fentanyl patches (Durogesic). Basically, blood concentrations in postmortem specimens cannot be directly compared with in vivo serum levels: in our study, we observed that postmortem fentanyl blood concentrations were on average up to nine times higher than in vivo serum levels at the same dose. These differences could be explained by postmortem redistribution, but they were higher than expected on the basis of the physical and chemical properties of fentanyl alone. The special pharmacokinetics of the drug after long term transdermal application seem to play an important role in this phenomenon. In addition, there was no clear correlation between transdermal fentanyl dose and blood or serum concentrations, either antemortem or postmortem. Our study provides extensive data for postmortem peripheral blood concentrations after therapeutic non-fatal fentanyl patch application and demonstrates once more that in forensic toxicology, blood concentrations must be holistically interpreted with respect to all aspects of a case.

Acute intoxication with aniline: detection of acetaminophen as aniline metabolite.

Abstract A 47-year-old woman unwittingly ingested an unknown substance together with her breakfast coffee. She suffered effects such as strong headache, generalized cyanosis, and a burning sensation of the lips and collapsed some minutes later. After admission into hospital a methemoglobin level of 35% was determined in the blood. Treatment by administration of tolonium chloride (toluidine blue) resulted in complete recovery of the patient. The toxic agent was identified as aniline by GC with mass selective detection after organic solvent extraction and 11 h after ingestion the plasma aniline level was 0.13 mg/l. Acetanilide (0.79 mg/ml) and acetaminophen (2.3 mg/ml) were identified in plasma as metabolites of aniline. It was assumed that a high metabolic capacity for acetylation protected the victim from more severe reactions. Her husband confessed later that he had tried to poison her.

Analysis of cyclosporin a in hair samples from liver transplanted patients.

Introduction: Cyclosporin A (CsA) is one of the most important immunosuppressants currently used to prevent organ rejection after liver transplantation. Therapeutic benefit and adverse toxicity are associated with only small differences in CsA blood concentration. Correct individual dosage and compliance are therefore essential for successful therapy. To this end, we developed a validated analytical assay for the determination of CsA in hair samples. Hair samples from patients treated with CsA after liver transplantation were analyzed to investigate correlations between hair concentrations, blood concentrations, and CsA doses. The aim of this study was to evaluate whether hair analysis could be useful for the long-term follow-up of liver transplantation patients. Materials and Methods: Hair samples from patients were segmented and decontaminated. After alkaline hydrolysis and liquid–liquid extraction, CsA was analyzed by liquid chromatography–tandem mass spectrometry. Results: The peptide CsA (molecular weight 1202.6 Da) was detected in all the patient hair segments corresponding to times of CsA intake, whereas all hair segments reflecting times without CsA treatment tested negative. Correlation between CsA hair concentrations and CsA doses was poor. Consequently, it was not possible to verify the amount of CsA intake by hair analysis. A correlation coefficient of r2 = 0.57 was found for the correlation of average whole blood trough concentrations and hair concentrations. The segmental CsA hair concentrations were found to be much steadier than the whole blood trough concentrations. In patients with stable or slightly changed CsA dosages, a comparable segmental concentration profile with a decrease in CsA hair concentrations from proximal to distal was found. Major modifications in CsA dosage are followed by a corresponding trend in segmental hair concentrations. Conclusions: Our results suggest that it is not possible to quantify the amount of CsA intake by hair analysis. Segmental hair analysis might be useful in the detection of substantial noncompliance and to detect changes in drug-taking behavior.

Determination of ethyl glucuronide in human hair samples: A multivariate analysis of the impact of extraction conditions on quantitative results

BACKGROUND Ethyl glucuronide (EtG), a minor metabolite of ethanol, is used as a direct alcohol biomarker for the prolonged detection of ethanol consumption. Hair testing for EtG offers retrospective, long-term detection of ethanol exposition for several months and has gained practical importance in forensic and clinical toxicology. Since quantitative results of EtG hair testings are included in interpretations, a rugged quantitation of EtG in hair matrix is important. As generally known, sample preparation is critical in hair testing, and the scope of this study was on extraction of EtG from hair matrix. METHODS The influence of extraction solvent, ultrasonication, incubation temperature, incubation time, solvent amount and hair particle size on quantitative results was investigated by a multifactorial experimental design using a validated analytical method and twelve different batches of authentic human hair material. Eight series of extraction experiments in a Plackett-Burman setup were carried out on each hair material with the studied factors at high or low levels. The effect of pulverization was further studied by two additional experimental series. Five independent samplings were performed for each run, resulting in a total number of 600 determinations. RESULTS Considerable differences in quantitative EtG results were observed, concentrations above and below interpretative cut-offs were obtained from the same hair materials using different extraction conditions. Statistical analysis revealed extraction solvent and temperature as the most important experimental factors with significant influence on quantitative results. The impact of pulverization depended on other experimental factors and the different hair matrices themselves proved to be important predictors of extraction efficiency. CONCLUSIONS A standardization of extraction procedures should be discussed, since it will probably reduce interlaboratory variabilities and improve the quality and acceptance of hair EtG analysis.

Vergiftungs- und Todesfälle durch Substitutionsmittel im Umfeld von substituierten Drogenabhängigen

Abstract A total of seven cases of accidental ingestion of methadone or dihydrocodeine by four children and three adults are reported of which four were fatal. In each case, someone in the environment was taking methadone or dihydrocodeine as a substitute drug for heroin addiction who obviously did not realize the dangers of methadone for non-addicts. Possible preventive measures are the usage of child-proof containers with adequate labels for take-home medications. Furthermore substituted addicts have to be thoroughly indoctrinated concerning the toxicity and hazards of methadone.Zusammenfassung Es wird über 3 überlebte und 4 tödlich verlaufene akzidentelle Intoxikationen, sechs mit Methadon, eine mit Dihydrocodein, berichtet. Die Intoxikationen betrafen nicht die Substituierten selbst, sondern deren Familienangehörige, Bekannte oder Mit-Patienten. In allen Fällen wurden die Substitutionsmittel weitgehend ungesichert und teilweise vermutlich auch unbeschriftet stehengelassen. Den Substituierten selbst war dabei die Gefahr, die von ihrem Substitutionsmittel ausging, offenbar nicht ausreichend bewußt. Diese Fälle zeigen deutlich, daß qualitätssichernde Maßnahmen bei der immer großzügigeren Substitutionspraxis, insbesondere in Hinblick auf „take-home“-Dosen, notwendig sind.

Uptake of Gamma-Valerolactone—Detection of Gamma-Hydroxyvaleric Acid in Human Urine Samples

Gamma-valerolactone (GVL) is reported to be a substance that can be used as a legal substitute for gamma-hydroxybutyric acid (GHB), which is currently a controlled substance in several countries. Unlike gamma-butyrolactone and 1,4-butanediol, GVL is not metabolized to GHB, which causes the effects after uptake of these two chemicals. In the case of GVL, the lactone ring is split to gamma-hydroxyvaleric acid (GHV or 4-methyl-GHB) by a lactonase. Because of its affinity for the GHB receptor, GHV reveals similar effects to GHB, although it is less potent. Intoxications with GVL, or its use as a date rape drug, are conceivable. Despite these facts, there are no publications in the literature regarding detections of GHV in human samples. This study reports three cases, including five urine samples, in which GHV could be detected in concentrations between 3 and 5.8 mg/L. In one of these cases, a drug-facilitated sexual assault (DFSA) was assumed; four of these samples were from two people suspected of abusing GHB. The results indicate that GVL is used as an alternative to GHB and its precursors and should be taken seriously. GVL or GHV should be included in toxicological analysis, particularly in DFSA cases. More information is needed regarding the pharmacokinetics of GVL/GHV for the meaningful interpretation of positive or negative results.

Correction to: Mass poisoning with NPS: 2C-E and Bromo-DragonFly

The original version of this article contains an error. The Author S. Lehmann incorrectly listed as S. Lehman. The correct spelling is presented above. The original article has been corrected.

Ethyl Glucuronide in Alcoholic Beverages

Aims This study examines the biomarker ethyl glucuronide (EtG) in various alcoholic beverages. Short summary The biomarker EtG was consistently found to be a natural compound of wine, whereas it was not detected in any of the other tested alcoholic beverages, which included various distilled spirits, liqueurs and beer of different types and geographical origins. Methods Alcoholic beverages (n = 114) were analyzed by a validated liquid chromatography/tandem mass spectrometry assay. Beverages included samples from beer, wine, liqueurs and spirits from different manufacturers and geographical origins. Results EtG was not detected in any kind of distilled alcoholic beverages, regardless of the type of spirit (rum, gin, vodka, whiskey, fruit brandy, corn brandy, cordial) or liqueur (n = 52). EtG was also not detected in any of the analyzed samples of beer, which included pilsener, weissbier, lager beer and ale from different origins (n = 20). In contrast, EtG was detected in every of the analyzed samples of wine (n = 42) without exception. Highest amounts were found in red wine and ranged from 1425 to 3720 μg/l (n = 16). Significantly, lower concentrations of EtG were observed for white wine (347-1685 μg/l, n = 14) and sparkling wine (281-1447 μg/l, n = 10). Conclusions Wine is an external source of EtG. It has been shown that milligram amounts of the biomarker can be contained in a bottle of wine. This should be considered in biomarker testing, especially in EtG hair analysis, which is susceptible to external contamination.