Olanzapine-induced hyperglycemic ketoacidosis and corresponding acetone concentrations post-mortem: a forensic interpretation

Olanzapine has been shown to cause or have a contributory role in the development of hyperglycemia and diabetes mellitus. Without careful monitoring for the development of these conditions and control of the resulting adverse effects, patients receiving olanzapine may be at risk of developing fatal ketoacidosis. A review of post-mortem toxicological reports has revealed an increase in the incidence of post-mortem findings of acetone in decedents who were taking olanzapine over the past decade. A review of the current literature and a comprehensive review of case histories and toxicological findings were conducted at the Centre of Forensic Sciences (Toronto, Ontario). Olanzapine concentrations ranging from <62.5 to 858 ng/mL and acetone concentrations as high as 95 mg/dL were detected concurrently. Due to the unstable nature of olanzapine, in several instances quantitation was not possible despite elevated responses during qualitative screening procedures. Five cases suggesting olanzapine-induced ketoacidosis were identified based on the case history and toxicological findings. These data have been compiled and examined with respect to acetone concentrations following olanzapine use and the forensic relevance of post-mortem olanzapine and acetone concentrations are discussed.     

法医毒物检验技术方法的评价方式

评价方式是评价技术中的重要组成部分。根据法庭科学领域毒物检验方法的技术特性与质量要求,在明确评价目标与原则的基础上,以评价指标为核心提出合理化的、可操作的评价方式。建立有效的评价方式,旨在通过科学的评价活动获得客观的评价结果。     

Subacute fatal aluminum poisoning in dialyzed patients: post-mortem toxicological findings

The population of Cura?ao, Netherlands Antilles (133,000) shows a very high prevalence of end-stage renal disease (approximately 1 per 1,000). These patients are often treated chronically with haemodialysis. As the drinking water on the island is prepared by distillation of sea water, the haemodialysis fluid used to be prepared with tap water without further treatment. In 1996, the 27 patients of one of the dialysis centers on the island presented with nausea, vomiting, and hypercalcaemia in a short time span, which was initially diagnosed as 'hard water syndrome'. In spite of treatment with low-calcium dialysate, microcytic anaemia and neurological symptoms developed. Ten patients died of convulsions, sepsis, and coma. As aluminum (Al) intoxication was suspected, Al in serum (AlS) was measured. Ante mortem AlS was 808 microg/l (n = 7; range 359-1189); in the survivors AlS was 255 microg/l (n = 17; range 113-490). Normal AlS is < 10 microg/l, and <50 microg/l in asymptomatic dialyzed patients. The court requested post-mortem toxicological analysis of four patients. Al concentrations in liver, bone, and cerebral cortex were significantly increased as compared with background levels. Al intoxication was, therefore, considered to be the most likely cause of death in these patients. Investigations of the tap water supply revealed that a few weeks before the onset of the symptoms, a water conduit pipe to the dialysis unit had been replaced, which was lined with Al- and Ca-rich cement mortar. These ions leached into the distilled water and caused both Ca- and Al-intoxication through uptake from the dialysate into the patients' circulation. The symptoms of the latter were initially not recognized as they were masked by the symptoms of hypercalcaemia.     

A study of the shape of the post-mortem cooling curve in 117 forensic cases

The shape of the post-mortem cooling curve is described and its theoretical aspects are summarised. The concepts of the "infinite cylinder" and the "initial temperature plateau" are explained and their practical implications are discussed. Results of the study of the shape of post-mortem cooling curves for the brain, liver and the rectum of 117 cases are given. The bodies were monitored either naked or covered with blankets. For each case, temperatures of the three body sites and the environment were monitored soon after death and up to many hours post-mortem. Empirically derived three-exponential formulae were used in this study. The cooling curves for the three body sites were found to be of compound shapes and the slopes of the curves vary throughout the monitoring period. The "initial temperature plateau" was found on average in 22% of all cooling curves with the plateau incidence being significantly highest in the rectal curves (27% of rectal curves compared with 7% of brain and liver curves, P<0.1%). The effect of body sites, body build and covering of the torso on the occurrence of the plateau is assessed and discussed.     

法医毒物检验技术方法的质量要求

本文通过对73个法医毒物检验方法进行综合分析,从技术方法的质量特性上对方法的建立与确认提出质量要求.即从内部质量和外部质量的角度,针对法庭科学领域毒物检验技术方法,阐述其功能性、可靠性、易用性和有效性四个维度要求.     

Computer-assisted interpretation in forensic toxicology: morphine-involved deaths

Case data from 200 morphine-involved deaths (Spiehler, V. and Brown, R., Journal of Forensic Sciences, Vol. 32, No. 4, July 1987, pp. 906-916) were analyzed for patterns and relationships using artificial intelligence (AI) computer software. Case parameters were blood unconjugated morphine, blood, brain, and liver total morphine, sex, age, frequency of use, time of death after injection, cause of death, and presence of other drugs. The programs used were Expert 4 (Biosoft-Cambridge), BEAGLE (Warm Boot, Ltd.), and KnowledgeMaker (Knowledge Garden Inc.). Interpretation was defined as estimating the dose, response, and time after drug dosing. The AI programs were used to advise on time and response outcomes for cases, to calculate the probability of the estimate being true, to develop rules for interpretation of morphine-involved cases, and to diagram a decision tree. On known cases the AI programs were successful 70 to 90% of the time in classifying the cases as to response and time. No data on dose were available in this database. The success rate in individual cases was proportional to the program-estimated probability. All three programs found the case parameters of most value in predicting response to be blood unconjugated morphine, blood total morphine, and liver total morphine. The case data most useful in estimating time of death since drug injection were blood unconjugated morphine, percent unconjugated morphine in blood, and brain total morphine. The rule induction programs found that morphine overdoses were characterized by blood unconjugated morphine greater than 0.24 micrograms/mL, liver morphine greater than 0.50 to 0.75 micrograms/g, brain morphine greater than 0.08 micrograms/g or greater than blood unconjugated morphine, and percent blood unconjugated morphine greater than 37%. Rapid deaths were characterized by percent unconjugated morphine greater than 44 to 50%; blood unconjugated morphine, as a function of other drugs present, greater than 0.09 to 0.21 micrograms/mL; and brain total morphine greater than 0.16 to 0.22 micrograms/g. This work demonstrates that inexpensive AI programs commercially available for personal computers can be useful in interpretation in forensic toxicology.     

Fly larvae: a new toxicological method of investigation in forensic medicine

Toxicological analyses on a putrefied cadaver are sometimes difficult to achieve because of the absence of blood and urine. In this study, maggots, living material, are proposed as a new medium of investigation in forensic medicine. Five drugs (triazolam, oxazepam, phenobarbital, alimemazine, and clomipramine) were identified and assayed in some tissues of a putrefied cadaver and in the maggots found on and in the body.     

Studies on fluorescamine: Part I--Applications of fluorescamine in forensic toxicological analysis.

This paper describes some applications of the fluorescamine spot test to forensic toxicological analysis. The fluorescamine test only reacts with primary amines; thus, this test makes a clear-cut distinction between amphetamine and methamphetamine. Previous common spot tests used reacted the same with these two amines. Fluorescamine is 100 times more sensitive in detecting amphetamine extracted from urine on thin-layer chromatograms than ninhydrin. Thus, it is a more sensitive method of detecting amphetamine abuse in urinalysis screening programs.     

Acute arsenic poisoning: clinical, toxicological, histopathological, and forensic features

This report describes a suicide case by acute arsenic intoxication via intravenous injection. A 30-year-old woman injected arsenic As (V) (sodium arseniate disodique: Disodium Hydrogena Arsenik RP) in a successful suicide attempt. Three hours following administration, the woman developed severe digestive symptoms. She was admitted to a hospital and transferred to the intensive care unit within 12 h of the massive administration of arsenic. Despite therapeutic efforts, over the next 2 h she developed multiorgan failure and died. A postmortem examination was performed. Pulmonary edema and congestion of liver were apparent. As (V) and As (III) were determined by high performance liquid chromatography and inductively coupled plasma mass spectrometry after mineralization of samples by concentrated nitric acid. Toxicological analysis revealed high concentrations of arsenic in biological fluids as well as in organs. Histopathological examination showed a typical indication of myocarditis. These findings were in agreement with acute arsenic poisoning. The symptoms developed by this young woman (intoxication by intravenous administration) were comparable to oral intoxication. The clinical signs, survival time, and administration type are discussed in light of the literature on acute and chronic arsenic poisoning.     

Postmortem vitreous Beta-hydroxybutyrate: interpretation in a forensic setting*

Abstract: Vitreous beta‐hydroxybutyrate (BHB) was retrospectively analyzed in 1795 forensic cases using the Pointe Scientific method. Comparison of vitreous BHB with vitreous glucose in 1781 of the cases showed moderately good correlation r = 0.731. Comparison with blood alcohol levels in 1561 of the cases showed no correlation r = ?0.053. Vitreous BHB was a marker of diabetic ketoacidosis when above 6.0 mM with a vitreous glucose over 200 mg/dL. It was an indicator (>50%) for alcoholic ketoacidosis when above 6.0 mM with a vitreous glucose below 200 mg/dL. Recommendations for interpretation of vitreous BHB: <0.4 mM normal; 0.41–1.2 mM slightly elevated, rarely (<1%) of concern; 1.21–2.0 mM moderately elevated, less rarely (2.5%) of concern; 2.01–6.0 mM significantly elevated, frequently of concern (12–48%); >6.0 mM usually (100% in this study) indicated life‐threatening conditions. Vitreous BHB was helpful evaluating cases with ketogenic conditions, especially diabetes and alcoholism.     

Virtual forensic entomology: improving estimates of minimum post-mortem interval with 3D micro-computed tomography

We demonstrate how micro-computed tomography (micro-CT) can be a powerful tool for describing internal and external morphological changes in Calliphora vicina (Diptera: Calliphoridae) during metamorphosis. Pupae were sampled during the 1st, 2nd, 3rd and 4th quarter of development after the onset of pupariation at 23 °C, and placed directly into 80% ethanol for preservation. In order to find the optimal contrast, four batches of pupae were treated differently: batch one was stained in 0.5M aqueous iodine for 1 day; two for 7 days; three was tagged with a radiopaque dye; four was left unstained (control). Pupae stained for 7d in iodine resulted in the best contrast micro-CT scans. The scans were of sufficiently high spatial resolution (17.2 μm) to visualise the internal morphology of developing pharate adults at all four ages. A combination of external and internal morphological characters was shown to have the potential to estimate the age of blowfly pupae with a higher degree of accuracy and precision than using external morphological characters alone. Age specific developmental characters are described. The technique could be used as a measure to estimate a minimum post-mortem interval in cases of suspicious death where pupae are the oldest stages of insect evidence collected.     

QuEChERS方法在法医毒物分析领域的研究进展

在中毒或疑似中毒案件中,毒物鉴定对于提供侦查线索与犯罪证据、澄清案件性质、还原犯罪过程具有重要意义。基于液液萃取和分散固相萃取原理而建立起来的QuEChERS方法,由于其快速、简单、廉价、高效、可靠、安全等优势,正逐渐应用于法医毒物分析的样品前处理过程中。本文综述了QuEChERS方法的基本原理及其在提取和净化等过程中的优化改进,重点详述近年来QuEChERS方法在法医毒物分析领域的应用现状,并对未来发展方向进行展望。     

Fatal intoxications in the Nordic countries. A forensic toxicological study with special reference to young drug addicts

Fatal intoxications in the 15-34 age group in the five Nordic countries during the years 1984 and 1985 (Sweden only in 1984) were investigated. The known drug addicts were studied separately. The highest incidence of intoxications, calculated per 10(5) population, was found in Finland (11.3), followed by Denmark (10.3), Sweden (8.5), Iceland (7.2) and Norway (6.6). The percentage of intoxications caused by drugs was 92 in Denmark, 71 in Norway, 66 in Sweden, 50 in Finland and 17 in Iceland. Ethanol intoxications were seen 5-7 and 2-3 times as frequently in Finland and in Iceland, respectively, than in the other three countries. Carbon monoxide intoxications accounted for two-thirds of all fatal intoxications in Iceland. Drug addicts accounted for 62% of all fatal intoxications in the Danish material. The corresponding figures were 33% in the Norwegian, 16% in the Swedish and 5% in the Finnish material. No deaths in drug addicts were found in Iceland. Most drug addicts in Denmark, Norway and Sweden died of hard drugs and most in Norway and Sweden, from heroin or morphine, whereas in Denmark other strong analgesics, such as methadone, dextropropoxyphene and ketobemidone, accounted for 40% of all hard-drug-related fatal intoxications. To a certain extent the results reflect differences in the legal autopsy routines in the various Nordic countries. However, the ascertainment of drug addicts is assumed to be near-complete in each country.     

Cytochrome P450 2D6 (CYP2D6) genotyping on postmortem blood as a supplementary tool for interpretation of forensic toxicological results

Debrisoquine hydroxylase (CYP2D6) is involved in the metabolism of many toxicologically important drugs. The gene encoding for this enzyme displays a polymorphic distribution in all populations examined. We report a study on 46 cases, where analyses of the CYP2D6 gene were conducted on postmortem femoral blood in order to investigate the occurrence of poor metabolizers (PM). A polymerase chain reaction (PCR) method, designed and routinely used for therapeutic drug monitoring, was employed, only slightly modified. Samples from 22 cases, where the parent drug to metabolite ratio was unexpectedly high were analyzed as well as samples from 24 control cases. Genotyping could be carried out in all but one case. Previous freezing or addition of potassium fluoride as preservative did not prevent analysis. Only one PM (from the control group) was discovered, implying an occurrence of only 2.2% as compared to the reported frequency of approx. 7% in Sweden. Among the extensive metabolizers (EM), however, a number of individuals with mutated genes were identified. Although it seems reasonable to suspect a PM genotype in cases with a high concentration of a drug metabolized by CYP2D6, but without suspicion of acute overdose, our study does not support the opinion that this interpretation pitfall is particularly common. This study rather indicates that drug interactions in EMs constitute a more frequent and important problem.     

Effect of post-mortem changes on peripheral and central whole blood and tissue clozapine and norclozapine concentrations in the domestic pig (Sus scrofa)

Interpretation of the results of psychoactive or other drug measurements in post-mortem blood specimens may not be straightforward, in part because analyte concentrations in blood may change after death. There is also the issue of comparability of plasma (or serum) results to those obtained in whole blood. To investigate these problems with respect to clozapine, this drug (10mg/kg daily) was given orally to two pigs. Blood was collected 3h post-dose on day 7, the animals were sacrificed, and blood taken from central and peripheral veins for up to 48 h after death. Tissue samples were also collected immediately after death and at 48 h. Ante-mortem whole blood clozapine/N-desmethylclozapine (norclozapine) concentrations were 0.86/1.07 and 1.11/1.15 mg/l in pigs 1 and 2, respectively. Blood clozapine and norclozapine concentrations generally increased after death (central vein: clozapine up to 300%, norclozapine up to 460%; peripheral vein: clozapine up to 155%, norclozapine up to 185%). Initial blood and kidney clozapine and norclozapine concentrations were comparable in both animals, but were some two-fold higher in heart, liver and striated muscle in pig 2. In both animals, the heart and striated muscle clozapine and norclozapine concentrations had increased some two- to three-fold at 48 h, whilst the liver and kidney concentrations were essentially unchanged. The reason for the increase in heart and striated muscle concentrations at 48 h is unclear, but could be simple variation in sample site. The plasma:whole blood distribution of clozapine and norclozapine was studied in vitro. In human blood (one volunteer donor, haematocrit 0.50) the plots of plasma versus whole blood concentration were linear for both analytes across the range 0.1-1.5mg/l, although clozapine favoured plasma (plasma:whole blood ratio=1.12), whereas norclozapine favoured whole blood (ratio 0.68). In pig blood, the plots of plasma versus whole blood were non-linear in both cases, although clozapine favoured plasma to a greater extent than norclozapine. This may be due to lower plasma clozapine and norclozapine protein binding capacity in the pig as compared to man.