Determining the Toxicological Significance of Pregabalin in Fatalities

Pregabalin has become more widely prescribed and abused in recent years but is still not always included in laboratory analysis. An LC‐MS‐MS method has been developed and applied to measure pregabalin in 93 postmortem cases, including drug‐related deaths, alternative causes of death, and fatalities where pregabalin was likely to have contributed to death. Other drugs or alcohol was detected, and the most common drug types (in decreasing frequency) were antidepressants, opioids, benzodiazepines, opiates, alcohol, antipsychotics, cocaine, cardiac drugs, amphetamines, cannabis, anticonvulsants, and antihistamines. New psychoactive substances (methoxphenidine and synthetic cannabinoids) were only found in two cases. The results provide further data to assist in evaluating the significance of postmortem pregabalin concentrations and a toxicologically significant concentration of 25 mg/L is proposed. Pregabalin, especially with concomitant use of other CNS depressant drugs, presents a significant toxicological risk and existing laboratory protocols should be reviewed for their suitability to detect pregabalin.     

Urinary catecholamines in hyperthermia-related deaths

A group of five hyperthermia-related deaths is presented in which urinary noradrenaline (NA) concentrations were elevated (172.1 +/- 119.4 ng/ml) compared with a control group of rapid violent deaths (43.7 +/- 26.1 ng/ml). Urinary adrenaline (A) concentrations were not elevated in the hyperthermia cases, nor were there any significant differences in urinary dopamine (DA) concentrations between the two groups. All except one of the hyperthermia victims were under the influence of ethanol. It is suggested that a combination of heat stress and ethanol consumption was responsible for the elevated urinary NA in the hyperthermia cases, reflecting increased sympathetic nervous system activity. A combination of high urinary NA with low A seems to be characteristic of hyperthermia fatalities, in contrast to hypothermia deaths, where both NA and A are usually elevated.     

Fatalities associated with the termination of electrical services

The worldwide dependence on electricity to support the needs of today's society is often taken for granted and, as such, the hazards associated with the termination of electrical services are often neglected. Whether electrical services are unintentionally terminated as the result of severe weather or intentionally terminated as the result of nonpayment of utility bills, the ensuing conditions may lead to injury or death in affected individuals. We performed a retrospective review of all deaths investigated by the Onondaga County Medical Examiner's Office between 1999 and 2004. Our case database was searched for causes of death that included hypothermia, hyperthermia, carbon monoxide, fire, electrocution, and/or electricity. Further review of these cases was undertaken to determine the potential relationship between the death and the termination of electrical services. Seven fatalities were found to be associated with the termination of electrical services. Four fatalities resulted from its unintentional termination and 3 were a consequence of intentional termination. In reporting these deaths, we hope to emphasize the potential dangers associated with the termination of electrical services and explore the informational programs and public health laws that are in place to limit the associated potential negative outcomes.     

Toxicological findings in Federal Aviation Administration general aviation accidents

Blood, urine, and tissue specimens were received from 377 Federal Aviation Administration (FAA) aviation fatalities during fiscal year 1989. Carbon monoxide at less than 10% saturation was found in 94% of the cases, and cyanide at less than 0.5 mg/L was found in 96% of the cases. Ethanol at greater than 10 mg/dL was found in 14.8% of the cases, but only 4.5% were determined to be due to ethanol ingestion from toxicological findings. Excluding nicotine and ethanol, 12.6% of the cases were positive for one or more drugs. Acetaminophen and salicylate were the most frequently found drugs. Cannabinoids were found in 1.3% of the cases and benzoylecgonine in 1.6%. There was minimal use of therapeutic drugs that cause central nervous system depression or stimulation. These results show no consistent pattern of drug involvement in civilian aviation fatalities.     

Immunohistochemical investigation of ubiquitin and myoglobin in the kidney in medicolegal autopsy cases

We examined the immunohistochemical distributions of ubiquitin (Ub) and myoglobin (Mb) in human kidney tissues to assist the pathological assessment of death due to trauma. Medicolegal autopsy cases at our institute (n=138: 0-96 years of age, 105 males and 33 females) were examined. Causes of death were blunt injury (n=31), sharp injury (n=15), poisoning (n=11), drowning (n=10), fire fatalities (n=25), hypothermia (n=7), asphyxiation (n=14), hyperthermia (n=3), and natural diseases (n=22) for controls. Immunostaining of Ub and Mb was performed on the formalin-fixed paraffin-embedded kidney tissue sections. Quantitative analyses by estimating the proportion of Ub- and Mb-positive cells (%positivity) of renal tubule epithelial cells showed that the positivities for Ub and Mb were higher in subjects who died due to fire, blunt injury, sharp injury and fatal hypothermia than in other groups. The Ub-positivity correlated with the severity of airway thermal injury in fire deaths, survival time in blunt injury, and serum markers for renal failure in deaths due to sharp injury. Concomitant increases in the tubular Mb- and Ub-positivities were characteristic to deaths from injury and hypothermia. These findings suggest that Ub may serve as a sensitive indicator of the fatal influence of traumas.     

Hypothermia-related Deaths: A 10-year Retrospective Study of Two Major Metropolitan Cities in the United States*

Hypothermia-related deaths affect vulnerable populations and are preventable. They account for the vast majority of weather-related deaths in the United States. The postmortem diagnosis of hypothermia can be challenging, as there are no pathognomonic signs. The electronic databases of the New York City Office of Chief Medical Examiner and Harris County Institute of Forensic Sciences were searched for all fatalities where the primary cause of death included hypothermia, between January 2009 and July 2019. There were 139 hypothermia deaths in New York City (NYC) with an average annualized rate of 1.7 per million. During this same time, there were 50 hypothermia deaths in Houston with an average annualized rate of 2.4 per million. Males were more likely to die of hypothermia compared to females in both cities. The rate ratio (RR) in NYC was 3.55 (95% CI 2.40, 5.25), while the RR in Houston was 2.83 (95% CI 1.50, 5.32). Age- and sex-specific standardized hypothermia mortality rates were 18.2 (95% CI 15.1, 21.2) per million in NYC and 30.1 (95% CI 21.7, 38.6) per million in Houston. The comparative hypothermia death ratio was 1.66 (95% CI 1.19, 2.30), indicating hypothermia mortality in Houston was 66% higher than in NYC. There was no correlation between zip code poverty rates and hypothermia-related deaths. The most consistent autopsy finding was Wischnewski spots (56.6%), and ethanol was the most common toxicological finding (36.5%). Local agencies can use this data to target these higher-risk populations and offer appropriate interventions to try to prevent these deaths.     

Occupational workplace and traffic fatalities in Alsace, France (2000–2005): Results of toxicological investigations

France ranks as leader country in Europe for the consumption of cannabis as well as of psychoactive medications. Whereas the relationship between psychotropics and road accidents is now well-established, few data are still available on the influence of drugs on occupational accidents. The purpose of the present study was to measure the prevalence of psychoactive drug intake (alcohol excepted) among victims of occupational fatalities (including workplace accidents + traffic accidents, i.e. on the way to and from work) occurred in the region Alsace over the period 2000–2005. Data were collected by compiling files on occupational accidents from two different public agencies (CRAM, Regional Sickness Fund Alsace-Moselle; DRTEFP, Regional Department of Work, Employment and Professional Training) together with those from the Medico-Legal Institute of Strasbourg over the period tested. Data analysis showed that 3% of the victims of workplace fatalities were under the influence of drugs (alcohol excluded) at the time of accident, as well as 5% of the victims of occupational traffic accidents. Our results also highlight a low rate of toxicological analyses, since these investigations were requested by the authorities in 41% of traffic victims and only 15% of workplace victims. In France, the relevance of psychoactive drug intake in occupational deaths is much better targeted in the case of traffic fatalities (due to the existence of specific regulations, e.g. compulsory urinalysis for drugs of abuse in drivers involved in a road accident) than in those occurred at workplace (no specific regulations).     

Accidental deaths caused by electricity in Sweden, 1975-2000

This study analyzes accidental fatalities caused by electricity--at work and during leisure time--to evaluate risk factors, the role of alcohol, and to identify possible preventive strategies. In Sweden, data on fatalities by electrocution from 1975 through 2000 were collected from the National Cause-of-Death Register. Additional cases were found in the archives of The Swedish National Electrical Safety Board. Suicides and deaths by lightning were excluded. Two hundred and eighty-five deaths were found, including occupational (n=132), leisure time (n=151), and unknown (n=2). Most deaths were caused by aerial power lines, and the most common place for an electrical injury was a railway area or residential property. Postmortem blood from 20% (n=47) of the tested cases was found positive for alcohol, and these persons were killed mainly during leisure time. During the study period, the overall incidence of electricity-related fatalities has decreased, in spite of increased use of electricity. This indicates that safety improvements have been successful.     

Death caused by drug addiction: a review of the experiences in Hamburg and the situation in the Federal Republic of Germany in comparison with the literature

Based on criminological experiences and pathomorphological, serological and toxicological studies of more than 300 fatalities, an overview is given of drugs, their intravenous abuse and drug deaths in Hamburg and the Federal Republic of Germany. The number of drug deaths has increased dramatically in Hamburg, where there were more than 50 cases each year in 1987 and 1988. In the F.R.G. approximately 400 cases are registered per annum. The percentage of female intravenous drug abusers is growing and the age of the decedents is increasing. The mean was formerly 25 years, but is now 30 years. Among the histopathological findings, foreign-body granulomas are of special value; infectious diseases, especially hepatitis B and HIV-infection, have to be investigated serologically and morphologically. The prevalence of HIV-1 antibodies among drug deaths in Hamburg is approximately 15%, in comparison with approximately 50% in Berlin. The "supply" of heroin has apparently become so copious that nearly all deaths are caused by overdosage with this substance. An international agreement about a definition of a drug death is a prerequisite for nationwide analyses.     

Hyperthermia deaths in Finland in 1970-86

All cases in which hyperthermia had been determined as the basic cause of death during the period 1970-86 were collected from the records of the Central Statistical Office of Finland. Of the total of 230 cases, 228 were included in the present study; the two remaining victims died abroad, and no autopsy was performed in Finland. Most of the hyperthermia deaths occurred while the decedent was taking a sauna bath; most decedents were men aged 42-62 years. An increase in the total number of hyperthermia deaths, and of male victims, was noted from the beginning of the 1970s onward; the number of female victims remained at a relatively steady level throughout, with the exception of a slight rise in 1986. Acute alcohol consumption was detected in most of the victims; in some cases there was also a reference to chronic alcoholism or recent long-term heavy drinking. The findings suggest that in addition to the acute hazardous effect of ethanol on thermoregulatory mechanisms, the long-term consumption of alcohol may have promoted fatal hyperthermia in these subjects.     

Toxicological findings in victims of traumatic deaths.

The toxicological findings from 6037 analyses of viscera obtained from victims of traumatic death are used to correlate the relative incidence of carbon monoxide, ethyl alcohol, narcotics, hypnotics, analgesics, and tranquilizers-antidepressants in deaths occurring under the following circumstances: fire related, asphyxia by hanging, by use of plastic bags, from physical obstruction of trachae, and by drowning; traumatic injury from impact of moving train, fall from height, and occupational accident; traumatic injury to pedestrian, driver, and passenger from vehicular accidents; and from violent death by shooting, stabbing, strangulation, and beating. The influence of alcohol, narcotic drugs, and tranquilizers on carbon monoxide can be seen in some of these traumatic deaths. Ethanol alone and in combination with other drugs was present in 42.3% and 19.5% of driver and pedestrian victims, respectively, of vehicular accidents in the year 1974. Comparative analysis is presented for the toxicological data obtained on victims of homicide (shooting, stabbing, strangulation, and beating) in New York City and similar data reported for victims of homicide in Detroit. In New York City 45.9% of such victims died while under the influence of alcohol or narcotic drugs, or both, with methadone predominating in the latter category. Tissue concentrations of drugs found in victims of traumatic death are presented. Diphenylhydantoin, diazepam, meperidine, and slow-acting barbiturates were found in normal therapeutic levels. Higher concentrations of amitriptyline, chlorpromazine, propoxyphene, short-acting barbiturates, and methadone were observed. The concentration of methadone in blood and brain (0.13 +/- 0.14 mg/100 ml) and in liver (0.53 +/- 0.42 mg/100 ml) in cases of traumatic death are not different from those observed in deaths classified as due to methadone overdose.     

Evaluation of human brain damage in fatalities due to extreme environmental temperature by quantification of basic fibroblast growth factor (bFGF), glial fibrillary acidic protein (GFAP), S100β and single-stranded DNA (ssDNA) immunoreactivities

Fatalities due to extreme environmental temperatures involving hypothermia (cold exposure) and hyperthermia (heat stroke) might present with poor or nonspecific morphological pathologies, which are insufficient to establish the cause of death in forensic practice. The present study immunohistochemically investigated basic fibroblast growth factor (bFGF), glial fibrillary acidic protein (GFAP), S100β and single-stranded DNA (ssDNA) in the parietal lobe and hippocampus of the brain in fatalities from hypothermia (n=15) and hyperthermia (n=18), and compared them to those of controls (n=39), including acute death due to ischemic heart disease, mechanical asphyxiation and drowning. In addition, S100β concentration in cerebrospinal fluid (CSF) was measured. Characteristic findings in hypothermia cases were higher glial bFGF immunopositivity in the cerebral cortex and white matter, and higher S100β immunopositivity in the cerebral cortex with a lower CSF S100β concentration. Hyperthermia showed lower glial GFAP and S100β immunopositivities in the white matter, and higher neuronal ssDNA immunopositivity in the cerebral cortex and hippocampus, accompanied by high glial bFGF and S100β immunopositivities in the cerebral cortex. These findings suggest neuroprotective glial responses without marked neuronal or glial damage in fatal hypothermia, and diffuse neuronal apoptosis despite initiation of neuroprotective cortical astrocyte responses, accompanied by glial damage in the white matter, in fatal hyperthermia. These markers may be useful for evaluating brain damage and responses in fatalities due to extreme environmental temperatures.     

Wide-bore capillary column gas chromatography in toxicological analysis of biological samples from multidrug overdoses fatalities

Fatalities from multidrug overdoses account for 25% of the total number of all poisoning fatalities and as such deserve greater attention from researchers than single drug overdoses. High resolution, good sensitivity, and repeatability provided by gas chromatography (GC) with wide-bore capillary silica and glass columns make GC particularly useful for identification and quantitative analysis of drugs in toxicological screening of autopsy specimens. Results of toxicological findings in three deaths from multidrug overdoses (methaqualone, doxepine, methotrimeprazine, pernazine-aspirin, paracetamol, codeine-morphine, diazepam) occurring in routine medical practice are reported.     

Fatal alcohol poisoning: medico-legal practices and mortality statistics

Compilation of mortality statistics from death certificate data is based on international and national conventions which in certain situations result in the underlying cause-of-death other than that established and reported by the physician. The present study compares all fatal alcohol poisonings in 1997 as registered on forensic toxicological grounds at the accredited central laboratory and as presented in the national cause-of-death statistics, according to the underlying cause-of-death, by applying international statistical rules and principles in ICD-10. Four groups were formed, and case frequencies in each group were obtained from forensic toxicological data, group "T51" for acute poisonings due to alcohol alone, and group "Comb" for acute alcohol poisonings combined with some drug, medicament or other biological substance, and from cause-of-death statistics data, group "X45", for deaths from alcohol poisoning, and group "F102" for those medico-legal fatal alcohol poisoning deaths which at the statistics office were inferred to be due to alcoholism. The study shows that in Finland the officially compiled statistics on fatal alcohol poisonings, when compared with medico-legal statements based on forensic toxicological examinations, were underrepresented by 31.4% in 1997. About two-thirds of this underrepresentation is explained by preferring, as the underlying cause-of-death, alcoholism to acute alcohol poisoning, and about one-third by preferring, in cases of acute combined poisonings, the drug component to the alcohol. From 1998 onwards, more emphasis has been put on the alcohol component when coding medico-legally proven accidental deaths from simultaneous poisoning with alcohol and a medicinal agent. This change in coding practices presumably explains the subsequent decline in the annual underrepresentation rate of alcohol poisoning in mortality statistics to the level of 15-16%. It is concluded that the present ICD rules inevitably lead to underrepresentation of alcohol poisonings in the mortality statistics, and conceptual and practical proposals for future procedures are made.     

Incidence of Fetal Drug Exposure in Alabama: 2004–2011

Postmortem toxicological results for neonates and stillborn fetuses were examined to determine the incidence of drug exposure in utero and the relationship to fetal mortality. From 15,600 fatalities with toxicological analyses, 39 subjects were identified; 22 had positive findings (56%). Among the general population, 10,500 had positive findings (67%). Among the subject population, 22 drugs/metabolites were identified; cocaine/benzoylecgonine was most frequent (9 of 22 cases, 41%) then methamphetamine/amphetamine (7 of 22 cases, 32%). Respective incidences among the general positive population were 12% and 6%. Fetal/neonatal concentrations overlap the general population and exceed the mother. Remaining substances, detected largely in fatalities unrelated to drug exposure, were of little toxicological significance. The variety, with exceptions, reflects the general population. That the incidence of cocaine and methamphetamine among fetuses/neonates is three‐ and fivefold greater than the general population is evidence that maternal abuse of these drugs poses greater risk to fetal viability than all other substances identified.     

Fatal intoxications in the age group 15-34 years in Denmark in 1984 and 1985. A forensic study with special reference to drug addicts

This survey deals with the Danish part of a study on fatal intoxications conducted in the Nordic countries in 1984 and 1985 with special reference to drug addicts. There were 315 cases of fatal intoxications in people 15-34 years of age. These were examined at the Forensic Institutes in Denmark and described with reference to cause of death, sex, age and drug addiction. Of the deceased, 194 were drug addicts according to a specific definition of this term. Women accounted for 28% of all the fatalities investigated in the study and 24% of those in addicts. More than 90% of the deaths were caused by drugs, with ethanol as a contributory factor in approximately 40% of cases. Deaths caused by heroin/morphine predominated, causing 50% of the deaths among drug addicts, but legal drugs, such as dextropropoxyphene, methadone and ketobemidone were also frequent causes of death in this group. In half the cases the concentration of morphine in blood following injection of heroin/morphine was found to be equal to or less than 0.5 mumol/kg, and in only about one-tenth of cases was the blood concentration above 2.0 mumol/kg.     

Screening analysis for medicinal drugs and drugs of abuse in whole blood using ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS)-Toxicological findings in cases of alleged sexual assault

An ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) method for simultaneous screening of 46 medicinal drugs and drugs of abuse in whole blood was developed and validated. The method includes most of the commonly used and abused drugs such as amphetamines, cocaine, benzodiazepines, and opioids. Chromatographic separation of the targeted drugs was achieved using a Waters ACQUITY UPLC coupled to a Waters Micromass LCT Premier XE time-of-flight mass spectrometer. The total chromatographic run time was 13.5min injection to injection. The estimated method LOQ is in the range of 0.06-27ng/g, which is below the therapeutic levels for each of the drugs analyzed but LSD. The extraction recovery ranged from 6% to 197% with median value 95% and mean value 82%. Matrix effect ranged from 81% suppression to 29% enhancement of the signals compared to signals obtained in the absence of biological matrix. The method was tested on 55 authentic forensic toxicology samples confirming the same positive results as found using the routine analytical procedures as well as some additional compounds. Recently there has been considerable attention paid to drug-facilitated sexual assault and the toxicological findings in these cases. As part of a pilot study to investigate the prevalence of medicinal drugs, drugs of abuse, and alcohol in victims of alleged sexual assault, biological specimens were obtained from 167 victims being examined at the Sexual Assault Center in Aarhus, Denmark. The obtained blood samples were analyzed using the novel screening method supported by additional analyses for e.g. THC and alcohol. 124 victims reported they have been drinking alcohol prior to the assault (74%). Alcohol analyses revealed 59 positive findings (48%). 35 of the cases were found positive for one or more drugs excluding alcohol (21%). 20 of the victims reported they have been subject to a drug-facilitated sexual assault (12%). For the victims suspecting drug-facilitated sexual assault, the toxicological analyses revealed four positive for alcohol and nine victims were positive for one or more drugs, with six of the victims found positive for benzodiazepines or other drugs with sedative effects. It was notable that victims tested positive for medicinal drugs and drugs of abuse as well as victims of alleged drug-facilitated sexual assault in average underwent medical examination later than the whole study population.     

The PMMA epidemic in Norway: comparison of fatal and non-fatal intoxications

During a 6 month period (July 2010-January 2011) we observed 12 fatal intoxications and 22 non-fatal cases related to the drug paramethoxymethamphetamine (PMMA) in Norway (4.8 mill inhabitants). This toxic designer drug, also known as "Death", is occasionally found in street drugs offered as "ecstasy" or "amphetamine". The present study aimed to evaluate the cause of death, and to compare the PMMA blood concentrations in fatal and non-fatal cases. Methods for identification and quantification of PMMA are presented. The median age of fatalities was 30 years (range 15-50) with 67% males; in non-fatal cases 27 years (20-47) with 86% males. In the 12 fatalities, the median PMMA blood concentration was 1.92 mg/L (range 0.17-3.30), which is in the reported lethal range of 0.6-3.1 mg/L in peripheral blood and 1.2-15.8 mg/L in heart blood. In the 22 non-fatal cases, the median PMMA concentration was 0.07 mg/L (range 0.01-0.65). Poly-drug use was frequent both in fatal and non-fatal cases. The PMA concentrations ranging from 0.00 to 0.26 mg/L in both groups likely represented a PMMA metabolite. Three fatalities were attributed to PMMA only, six to PMMA and other psychostimulant drugs, and three to PMMA and CNS depressant drugs, with median PMMA concentrations of 3.05 mg/L (range 1.58-3.30), 2.56 (1.52-3.23) and 0.52 mg/L (0.17-1.24), respectively. Eight victims were found dead, while death was witnessed in four cases, with symptoms of acute respiratory distress, hyperthermia, cardiac arrest, convulsions, sudden collapse and/or multiple organ failure. In summary, all fatalities attributed to PMMA had high PMMA blood concentrations compared to non-fatal cases. Our sample size was too small to evaluate a possible impact of poly-drug use. A public warning is warranted against use and overdose with illegal "ecstasy" or "speed" drugs.     

Determination of heroin after embalmment

A 30-year-old male died in Thailand after a scuffle. The corpse was embalmed and repatriated to France where an autopsy was performed. As usual in cases of embalmment, fluids such as blood and urine were unavailable and the toxicological analyses was performed on the bile and the liver. An overdose of heroin was determined as the cause of death. A review of the literature indicates that several drugs can be detected in fluids and tissues that contain formaldehyde. This case demonstrates that in embalmed corpses, toxicological assessment is still possible, e.g. after heroin fatalities.