Fatal tolperisone poisoning: autopsy and toxicology findings in three suicide cases

Tolperisone (Mydocalm) is a centrally acting muscle relaxant with few sedative side effects that is used for the treatment of chronic pain conditions. We describe three cases of suicidal tolperisone poisoning in three healthy young subjects in the years 2006, 2008 and 2009. In all cases, macroscopic and microscopic autopsy findings did not reveal the cause of death. Systematic toxicological analysis (STA) including immunological tests, screening for volatile substances and blood, urine and gastric content screening by GC-MS and HPLC-DAD demonstrated the presence of tolperisone in all cases. In addition to tolperisone, only the analgesics paracetamol (acetaminophen), ibuprofen and naproxen could be detected. The blood ethanol concentrations were all lower than 0.10 g/kg. Tolperisone was extracted by liquid-liquid extraction using n-chlorobutane as the extraction solvent. The quantification was performed by GC-NPD analysis of blood, urine and gastric content. Tolperisone concentrations of 7.0 mg/l, 14 mg/l and 19 mg/l were found in the blood of the deceased. In the absence of other autopsy findings, the deaths in these three cases were finally explained as a result of lethal tolperisone ingestion. To the best of our knowledge, these three cases are the first reported cases of suicidal tolperisone poisonings.     

Arsenic speciation of two specimens of Napoleon's hair

Since 1960, it has been demonstrated by various analytical procedures that high concentrations of arsenic were present in Napoleon's hair. Various authors, indicating that the detected arsenic levels are a consequence of external contamination, have challenged the results of these examinations. We have tested two strands of hair, referenced as Noverraz and Grand Maréchal Bertrand. Samples were incubated 6h in water at 90 degrees C, and arsenic speciation was carried out by HPLC-ICP/MS. The residue was injected on a cation-exchange PRP-X200 column that allows the detection of arsenobetaine and on an anion-exchange PRP-X100 column to test for the mineral forms. In these conditions, the inorganic species As(III), As(V) and their metabolites (DMA and MMA) were separated. Analysis of hair samples highlighted massive amounts of total arsenic (42.1 and 37.4ng/mg). Arsenical species found in the two samples of analyzed hair are distributed in the following: As(III) 31.1 and 44.7%; As(V) 66.3 and 53.2%; DMA 0.42 and 0.15%. Traces of MMA were detected, and 2% of the species could not be identified. These results prove that more than 97% of the arsenic found in the hair of Napoleon is in inorganic form, which is consistent with a chronic intoxication to arsenic.     

Arsenic speciation of two specimens of Napoleon's hair

Since 1960, it has been demonstrated by various analytical procedures that high concentrations of arsenic were present in Napoleon's hair. Various authors, indicating that the detected arsenic levels are a consequence of external contamination, have challenged the results of these examinations. We have tested two strands of hair, referenced as Noverraz and Grand Maréchal Bertrand. Samples were incubated 6 h in water at 90 °C, and arsenic speciation was carried out by HPLC–ICP/MS. The residue was injected on a cation-exchange PRP-X200 column that allows the detection of arsenobetaine and on an anion-exchange PRP-X100 column to test for the mineral forms. In these conditions, the inorganic species As(III), As(V) and their metabolites (DMA and MMA) were separated. Analysis of hair samples highlighted massive amounts of total arsenic (42.1 and 37.4 ng/mg). Arsenical species found in the two samples of analyzed hair are distributed in the following: As(III) 31.1 and 44.7%; As(V) 66.3 and 53.2%; DMA 0.42 and 0.15%. Traces of MMA were detected, and 2% of the species could not be identified. These results prove that more than 97% of the arsenic found in the hair of Napoleon is in inorganic form, which is consistent with a chronic intoxication to arsenic.     

Suicidal and accidental carbon monoxide poisonings due to charcoal fires in closed spaces

The number of fatal carbon monoxide poisonings has significantly decreased since the introduction of natural gas. Apart from their occurrence during house fires, accidental and suicidal carbon monoxide poisonings are only rarely seen nowadays. We report on 7 cases of unintentional and intentional fatal carbon monoxide poisoning (CO-Hb concentrations between 56.4% and 74%) due to improper handling of charcoal fires in closed spaces. Autopsy findings and results of the toxicological analysis are presented and discussed.     

Blood levels of 3-methylfentanyl in 3 fatal poisoning cases

Three fatal poisoning cases due to 3-methylfentanyl are described. In each case, the death was accidental and occurred after injection of the opioid combined with amphetamine, heroin, or other drugs. The victims' ages, ranging from 30 to 41 years, were higher than those typically found in heroin poisonings in Finland. The blood concentrations of cis-3-methylfentanyl, measured here for the first time by a specific tandem mass spectrometric method, ranged from 0.3 to 0.9 microg/L (mean 0.5 microg/L). These values are significantly lower than the levels reported for alpha-methylfentanyl and fentanyl in fatal poisonings. Repeated seizures of fentanyl and its analogs have been reported in Europe close to the Russian border.     

Comparison of blood-ethanol concentration in deaths attributed to acute alcohol poisoning and chronic alcoholism

Ethanol concentrations were measured in femoral venous blood in deaths attributed to acute alcohol poisoning (N = 693) or chronic alcoholism (N = 825), according to the forensic pathology report. Among acute alcohol poisonings were 529 men (76%) with mean age 53 years and 164 women (24%) with mean age 53 years. In the chronic alcoholism deaths were 705 men (85%) with mean age 55 years and 120 women (15%) with mean age 57 years. The blood-ethanol concentrations were not related to the person's age (r = -0.17 in acute poisonings and r = -0.09 in chronic alcoholism). The distribution of blood-ethanol concentrations in acute poisoning cases agreed with a normal or Gaussian curve with mean, median, standard deviation, coefficient of variation, and spread of 0.36 g/100 mL, 0.36 g/100 mL, 0.086 g/100 mL, 24% and 0.074 to 0.68 g/100 mL, respectively. The corresponding concentrations of ethanol in chronic alcoholism deaths were not normally distributed and showed a mode between 0.01 and 0.05 g/100 mL and mean, median, and spread of 0.172 g/100 mL, 0.150 g/100 mL, and 0.01 to 0.56 g/100 mL, respectively. The 5th and 95th percentiles for blood-ethanol concentration in acute poisoning deaths were 0.22 and 0.50 g/100 mL, respectively. However, these values are probably conservative estimates of the highest blood-ethanol concentrations before death owing to metabolism of ethanol until the time of death. In 98 chronic alcoholism deaths (12%) there was an elevated concentration of acetone in the blood (>0.01 g/100 mL), and 50 of these (6%) also had elevated isopropanol (>0.01 g/100 mL). This compares with 28 cases (4%) with elevated blood-acetone in the acute poisoning deaths and 22 (3%) with elevated blood-isopropanol. We offer various explanations for the differences in blood-ethanol and blood-acetone in acute poisoning and alcoholism deaths such as chronic tolerance, alcohol-related organ and tissue damage (cirrhosis, pancreatitis), positional asphyxia or suffocation by inhalation of vomit, exposure to cold coupled with alcohol-induced hypothermia, as well as various metabolic disturbances such as hypoglycemia and ketoacidosis.     

The Fatal Poisoning Pattern of Ankara (Turkey) and Nearby Cities from 2007 to June 2011: A Retrospective Study in Forensic Autopsies

We aimed to obtain an outline of the nature and number of fatal poisonings which still appear to affect widely the population in Turkey. A total of 5921 forensic autopsies were performed between 2007 and 2011 in Ankara and nearby cities and 366 of them were fatal poisonings (219 male, 147 female). Most of the cases were between 41 and 60 years old (n = 84). Most of the fatalities were reported during winter months (48.1%). Carbon monoxide exposure was the most common reason (66.7%) within all the causes followed by medicine and narcotics (13.9%). Postmortem blood alcohol concentrations in ethyl and methyl alcohol poisonings were 385.1 ± 61.9 and 206.8 ± 138.9 mg/dL, respectively. The most common location of deaths was home (71.3%). Fatal poisonings have been a growing global problem because of some shortcomings about the socioeconomic conditions and increasing illicit drug abuse. The level of education, socioeconomic conditions, and legal approaches are very important for the prevention fatal poisonings.     

Poisonings with diphenhydramine--a survey of 68 clinical and 55 death cases

The antihistaminic drug diphenhydramine (DPH) is mainly used as a sedative, hypnotic and antiemetic. In many countries it is over-the-counter available, very common, and generally regarded as a harmless drug. Sixty-eight non-fatal and 55 fatal poisonings with DPH alone or in combination with other drugs were investigated in the Institute of Legal Medicine of the University Hospital Charité between 1992 and 2004. The analytical investigations were performed by HPLC with photodiode array detector (HPLC-DAD). The DPH concentrations ranged from 0.5 to 8.9 microg/mL in the non-fatal cases and from 0.3 to 119 microg/mL in fatal cases. The intoxication symptoms stated during emergency admission were inconsistent, with somnolence, sedation and retardation on one hand and tachycardia, anticholinergic syndrome, agitation, hallucinations, confusion, tremor, convulsions, delirium and coma on the other. In three cases rhabdomyolysis occurred. A concentration above 5 microg/mL can be regarded as potentially lethal. In many of the survivors the time course of the concentrations of DPH and the metabolites desmethyldiphenhydramine (DM-DPH) and diphenylmethoxyacetic acid (DPMA) were investigated. Whereas DM-DPH is present in blood from the very beginning because of the high first pass metabolism, DPMA is slowly formed over several metabolic steps. For this reason, the concentration ratio DPMA/DPH can be used for an approximate estimation of the time between drug intake and sampling in clinical cases or of the survival time after drug ingestion in death cases. In some of the deaths the concentrations in heart blood were much higher than in venous blood. This is explained mainly by agonal aspiration of the vomited gastric content. Besides the majority of suicidal cases also a case of child maltreatment and a case, in which the drug was forcibly administrated in a drug facilitated crime, were investigated. From the results it follows that diphenhydramine is not less poisonous than other prescribed hypnotics. However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now.     

“Bath Salts” the New York City Medical Examiner Experience: A 3‐Year Retrospective Review

“Bath salts” are synthetic derivatives of cathinones, compounds found in the leaves of Catha edulis, which possesses amphetamine‐like properties. At the New York City Office of Chief Medical Examiner, we conducted a 3‐year retrospective analysis of deaths in which cathinones were detected. Two categories emerged; those in which cathinones were a contributory cause of death (15 cases) and those in which they were an incidental finding (15 cases). Of the former group, 13 were associated with additional intoxicants; two deaths were attributed solely to cathinone intoxication, both survived 10 h: a man whose postmortem blood methylone concentration was 0.71 mg/L and a woman whose postmortem blood ethylone concentration was 1.7 mg/L. In the latter category, there were several individuals who had higher concentrations of cathinones than the above two, the highest being a blood methylone of 4.8 mg/L. Based upon our data and the literature presented, lethal concentrations of cathinones cannot be established.     

Nutmeg (myristicin) poisoning--report on a fatal case and a series of cases recorded by a poison information centre

In literature, cases of nutmeg abuse have been described repeatedly, but only one fatal case of poisoning was reported [1]. In the present case, myristicin (4 microg/ml) was detected for the first time in the postmortal serum of a 55-year-old woman. Identification was achieved with the aid of UV-VIS spectroscopy and TLC; for quantification, HPLC was used. Because also flunitrazepam (0.072 microg/ml) was found, death had probably been due to the combined toxic effect of both substances. From 1996 to 1998, in a series of cases, seven poisonings with nutmeg were recorded by the Erfurt Poison Information Centre. Even where higher doses (20-80 g of powder) had been ingested, a life-threatening situation was never observed. In one of these cases, a myristicin blood level of 2 microg/ml was measured 8h after ingestion of two to three tablespoonful of nutmeg powder (approx. 14-21 g, or 280-420 mg/kg).     

Fatal intoxication due to tramadol alone: case report and review of the literature

Poisoning may also lead to both coma and multiple organ failure, also in youngsters without a known major medical history. As not all toxic agents are routinely screened when a poisoning is suspected, it is useful to consider less frequently encountered poisons in certain cases. We describe the occurrence of asystole and multiple organ failure which occurred in a young man after a suspected tramadol overdose. The tramadol concentration on admission in the ICU was indeed 8 microg/ml (mg/l), far above the therapeutic range. Subsequently, the patient developed severe acute liver failure, finally leading to death. Post-mortem toxicology did not reveal any other poison responsible for this unfavourable course as only very high serum and tissue tramadol and desmethyltramadol concentrations were found. Only a few fatal poisonings attributable to tramadol alone, as observed in our case, have been reported. An overview of these cases is presented.     

GHB. Club drug or confusing artifact?

GHB can be produced either as a pre- or postmortem artifact. The authors describe two cases in which GHB was detected and discuss the problem of determining the role of GHB in each case. In both cases, NaF-preserved blood and urine were analyzed using gas chromatography. The first decedent, a known methamphetamine abuser, had GHB concentrations similar to those observed with subanesthetic doses (femoral blood, 159 microg/ml; urine, 1100 microg/ml). Myocardial fibrosis, in the pattern associated with stimulant abuse, was also evident. The second decedent had a normal heart but higher concentrations of GHB (femoral blood, 1.4 mg/ml; right heart, 1.1 mg/ml; urine, 6.0 mg/ml). Blood cocaine and MDMA levels were 420 and 730 ng/ml, respectively. Both decedents had been drinking and were in a postabsorptive state, with blood to vitreous ratios of less than 0.90. If NaF is not used as a preservative, GHB is produced as an artifact. Therefore, the mere demonstration of GHB does not prove causality or even necessarily that GHB was ingested. Blood and urine GHB concentrations in case 1 can be produced by a therapeutic dose of 100 mg, and myocardial fibrosis may have had more to do with the cause of death than GHB. The history in case 2 is consistent with the substantial GHB ingestion, but other drugs, including ethanol, were also detected. Ethanol interferes with GHB metabolism, preventing GHB breakdown, raising blood concentrations, and making respiratory arrest more likely. Combined investigational, autopsy, and toxicology data suggest that GHB was the cause of death in case 2 but not case 1. Given the recent discovery that postmortem GHB production occurs even in stored antemortem blood samples (provided they were preserved with citrate) and the earlier observations that de novo GHB production in urine does not occur, it is unwise to draw any inferences about causality unless (1) blood and urine are both analyzed and found to be elevated; (2) blood is collected in NaF-containing tubes; and (3) a detailed case history is obtained.     

Carbon monoxide poisoning. Five-years' experience in a defined population.

A review is presented of 302 cases in East Denmark in 1982-1986 in which the manner of death was fatal carbon monoxide (CO) poisoning. The incidence of this far too frequent single-substance poisoning has as yet not decreased over the years despite preventive measures. The number of fatal CO poisoning cases may diminish as a result of a natural gas project in progress. The purpose of this survey, therefore, is to contribute to the evaluation of the actual causes of these fatal poisonings in East Denmark, and to discuss existing measures that prevent gas poisonings, in the expectation of a decline both in gas suicides and in accidental gas poisonings within the next few years.     

Postmortem citalopram concentrations: alone or along with other compounds

Citalopram, an antidepressant whose use has become more widespread in Spain in recent years participates directly and indirectly in the lethal mechanism in voluntary and involuntary poisonings. There were 30 cases of autopsies in the Madrid region where citalopram and other psychoactive substances (psychotropic drugs, alcohol, opiates) were detected in the corpses. The postmortem citalopram levels in relation to the manner and mechanism of death were evaluated, and a significant difference between the toxic and nontoxic cases (p < 0.01) was found. We studied the citalopram blood levels alone and along with other psychoactive products, and these cases were then further divided into those where the compounds were at deadly levels and those which were not. We found a range of citalopram levels between 0.37 and 0.83 microg/mL in which some cases were associated with citalopram toxicity and others were not. Citalopram blood levels of less than 0.35 microg/mL did not lead to fatal poisoning when it was the sole substance detected.     

The rise and rise of fentanyl in postmortem casework

Forensic toxicology laboratories are navigating a period of time with increasing drug overdose deaths, an opioid epidemic, the impact of the COVID-19 pandemic, and the illicit drug market flooded with novel psychoactive substances. In New York City, the Department of Forensic Toxicology has experienced a 56% increase in postmortem casework in the past decade with fentanyl detected in 80% of all overdose deaths. Over a period of 2.5 years, 15,638 postmortem cases were tested for the presence of fentanyl and fentanyl analogs using liquid-chromatography tandem mass spectrometry (LCMSMS). Fentanyl was detected in approximately one third of cases and of these 4447 cases with femoral blood. A twofold increase in cases with high concentrations of fentanyl (>100 ng/mL) was observed between 2021 and 2022. The minor metabolite and precursor chemical, 4-ANPP (4-anilino-N-phenethylpiperidine) may help differentiate between illicit and licit fentanyl. 4-ANPP blood concentrations were <10 ng/mL in 98% of the cases and the 4-ANPP:fentanyl ratio was <0.67 for 99.1% of blood specimens. Only six cases had 4-ANPP concentrations higher than the corresponding fentanyl blood concentration. This study also highlights, the changing fentanyl analogs found in postmortem cases since 2016 in NYC with the emergence of fluorofentanyl initially identified in 2020 and continuing to dominate in comparison with the prevalence of other analogs, many of which are no longer detected in casework. The detection of one of the latest drugs to be mixed with fentanyl, namely xylazine, has also increased in prevalence by 36.7% in 2022 compared with 2021.     

The relationship of methanol and formate concentrations in fatalities where methanol is detected

An automated headspace gas chromatography method was developed for the determination of formate (formic acid) in postmortem specimens, based on the in situ sulfuric acid-methanol methylation of formic acid to methyl formate. Diisopropyl ether was used as an internal standard. The method was applied to over 150 postmortem cases where methanol was detected. Of the 153 cases presented, 107 deaths were attributed to acute methanol toxicity. In the vast majority of the remaining 46 deaths, the methanol was determined to be present as a postmortem or perimortem artifact, or was otherwise incidental to the cause of death. Of the 76 victims who were found dead and blood was collected by the medical examiner, all but one had a postmortem blood formate concentration greater than 0.50 g/L (mean 0.85 g/L; n = 74). The sole exception involved suicidal ingestion of methanol where the blood methanol concentration was 7.9 g/L (790 mg/100 mL) and blood formate 0.12 g/L. In 97% (72/74) of the cases where blood was available, the blood formate was between 0.60 and 1.40 g/L. In 31 of the 153 cases, the victim was hospitalized and blood obtained on admission or soon after was analyzed for methanol and formate during the subsequent death investigation; the vast majority (27/30) had antemortem blood formate concentrations greater than 0.50 g/L. Cases with samples taken prior to death with blood formate concentrations less than 0.5 g/L can readily be explained by active treatment such as dialysis. The blood formate method has also been useful in confirming probable perimortem or postmortem contamination of one of more fluids or tissues with methanol (e.g., windshield washer fluid or embalming fluid), where methanol ingestion was unlikely.     

Toxic environmental factors in sudden infant death (SIDS)

The increasing number of discussions on the influence of toxic environmental factors, including SIDS, prompted systematic postmortem chemical-toxicological investigations to be carried out on 54 SIDS cases and 2 control cases of the same age group. Tissue levels of arsenic, lead, cadmium, mercury, and pentachlorphenol, as well as other organic noxious agents, were measured in several organs. In addition, the COHb concentrations were determined. In spite of the widely scattered values, the extreme levels measured and the arithmetic means and median averages of As, Pb, Cd, Hg, PCP, and COHb had no more range in concentrations than can be expected for toxic effects - according to present knowledge anyway. It was observed that infants from an urban environment showed no greater concentration of noxious agents than did infants from rural regions. There were also no differences between SIDS cases and the controls, nor was there a correlation between infections of the respiratory system that are often morphologically detected - including laryngitis - and higher concentrations of these agents in the organs of SIDS cases.     

Distribution of ethyl glucuronide in rib bone marrow, other tissues and body liquids as proof of alcohol consumption before death

Postmortem ethyl glucuronide (EtG) concentrations in rib bone marrow, liver, muscle, fat tissue, urine, blood and bile have been determined by LC-MS/MS. Samples have been taken from twelve corpses during autopsies. In nine corpses EtG could be detected, corresponding blood ethanol concentrations (BAC) were 0.04-0.37 g%. In three cases, no EtG was found; two of these cases showed postmortem BACs - possibly due to putrefaction - of 0.01 and 0.1g%. In rib bone marrow, which is easily accessible during autopsy, EtG concentrations (0.77-9.36 microg/g) have been lower than in blood (2.24-20.46 microg/mL) in eight of nine cases and comparable or higher than in muscle tissue. Therefore, rib bone marrow has been found suitable as matrix for EtG determination. The highest EtG concentrations have been found in urine in all but one case, where the resorption of ethanol had been incomplete. Second highest EtG concentrations have been detected in liver samples. In two cases with putrefaction, EtG could not be detected. In these cases, the detectable ethanol might have been produced partially or in total by postmortem fermentation. However, instability of EtG during putrefaction cannot be totally excluded which might result in a total loss of EtG.     

Fatal propane-butane poisoning

Two lethal poisonings by butane and propane are described, and the corresponding concentrations in the body fluids and organ tissues are evaluated. One case appeared to be an accident after deliberate inhalation for butane, one was a suicide. The mechanism of the inhalation could be reconstructed in both cases. The concentrations in the biological material agreed well with observations in similar cases.