Fatal flecainide intoxication

A fatal case attributed to flecainide acetate (Tambocor), a class Ic antiarrythmic drug, is presented. Flecainide was detected by GC/MS in gastric contents, blood and liver as well. The urine analysis revealed the presence of its dealkylated metabolite. Body fluids and tissue concentrations determined by GC/ECD were 7.7 mg/kg in femoral blood, 0.26 mg/kg in bile, 18 mg/kg in liver, 0.17 mg/kg in cerebrospinal fluid, 0.22 mg/kg in brain cortex and 28.9 mg/kg in urine. The total amount of flecainide in gastric contents was about 43 mg. Even taking into account the postmortem redistribution of flecainide, its blood level still remains in the toxic range.     

Fatal Overdose of Gamma‐hydroxybutyrate Acid After Ingestion of 1,4‐Butanediol

We report a case of fatal intoxication from 1,4‐butanediol (1,4‐BD), which was ingested by a young and “naïve” gamma‐hydroxybutyrate (GHB) consumer during a party with the co‐ingestion of alcohol, cannabis, and methylene‐dioxy‐methamphetamine. The following drug concentrations were found using gas chromatography coupled with mass spectrometry on autopsy samples and on a cup and a glass found at the scene: 20,350 mg/L (bottle) for 1,4‐BD; 1020 mg/L (femoral blood), 3380 mg/L (cardiac blood), 47,280 mg/L (gastric content), and 570 mg/L (vitreous humor) for GHB. The concentration of GHB is difficult to interpret in forensic cases due to the possibility of an endogenous production of GHB. The variable tolerance of the user may also modify the peri‐ and postmortem GHB concentrations. This case underscores the need to have many different sources of toxicology samples analyzed to avoid the hypothesis of endogenous production of GHB.     

Morbus Fahr--considerations on a case of sudden death

This paper presents 21 cases related to cyanide intoxication by oral ingestion. Cyanide concentrations in biological specimens are especially different from the type of postmortem specimens, and very important in interpreting the cause of death in postmortem forensic toxicology. Besides the detection of cyanide in autopsy specimens, the autopsy findings were unremarkable. Biological samples (0.2mL or equal to less than 10μg of cyanide) were analyzed colorimetrically for cyanide. In a series of 21 cyanide fatalities, the concentration ranges (mean±SD) of cyanide in heart blood, peripheral blood and gastric contents were 0.1-248.6mg/L (38.1±56.6mg/L), 0.3-212.4mg/L (17.1±45.1mg/L) and 2.0-6398.0mg/kg (859.0±1486.2mg/kg), respectively. The ranges of the heart/peripheral blood concentration ratio and gastric contents/peripheral blood concentration ratio were 0.3-10.6 (mean 3.4) and 3.4-402.4 (mean 86.0), respectively. From the difference of cyanide concentration and the concentration ratio of cyanide in different types of postmortem specimens, the possibility of the postmortem redistribution of cyanide and death by oral ingestion of cyanide could be confirmed. We reported cyanide fatal cases along with a review of literature.     

Fatal intoxication with 1,4-butanediol: Case report and comprehensive review of the literature

A fatal case of 1,4-butanediol (1,4-BD) oral ingestion is reported here, in which a 51-year-old man was found dead in his bed. According to the police report, the deceased was a known drug user. A glass bottle labeled (and later confirmed to be) “Butandiol 1,4” (1,4-BD) was found in the kitchen. Furthermore, the deceased's friend stated that he consumed 1,4-BD on a regular basis. The autopsy and histological examination of postmortem parenchymatous organ specimens did not revealed a clear cause of death. Chemical-toxicological investigations revealed gammahydroxybutyrat (GHB) in body fluids and tissues in the following quantities: femoral blood 390 mg/L, heart blood 420 mg/L, cerebrospinal fluid 420 mg/L, vitreous humor 640 mg/L, urine 1600 mg/L, and head hair 26.7 ng/mg. In addition, 1,4-BD was qualitatively detected in the head hair, urine, stomach contents, and the bottle. No other substances, including alcohol, were detected at pharmacologically relevant concentrations. 1,4-BD is known as precursor substance that is converted in vivo into GHB. In the synoptic assessment of toxicological findings, the police investigations and having excluded other causes of death, a lethal GHB-intoxication following ingestion of 1,4-BD, can be assumed in this case. Fatal intoxications with 1,4-BD have seldom been reported due to a very rapid conversion to GHB and, among other things, non-specific symptoms after ingestion. This case report aims to give an overview to the published of fatal 1,4-BD-intoxications and to discuss the problems associated with detection of 1,4-BD in (postmortem) specimens.     

Acute Benztropine Intoxication and Fatality

A woman was found unresponsive with an empty bottle of Cogentin^® prescribed to another. Admitted to an area hospital, her condition steadily declined until death 29 h after admission. Following toxicological screening on hospital (admission) whole blood, the only significant compound detected was benztropine. Benztropine was confirmed at 0.28 mg/L – the highest antemortem blood concentration recorded in a case of toxicity or fatality uniquely associated with benztropine. A second serum antemortem specimen showed a benztropine concentration of 0.19 mg/L. Despite over 24 h in the hospital, benztropine was also found in the postmortem specimens collected at autopsy. Peripheral blood, central blood, liver, and gastric concentrations were 0.47 mg/L, 0.36 mg/L, 9.6 mg/kg, and 44 mg, respectively. These results indicate that benztropine exhibited a potential difference between whole‐blood and serum (plasma) concentrations. Additionally, in consideration of literature data, benztropine was found indicative of a compound prone to at least some postmortem redistribution.     

A fatal dichlorvos poisoning: concentrations in biological specimens

Abstract:  A 54-year-old man was found dead with a bottle containing a brownish fluid near him. A toxicological screening was carried out in blood, urine, and stomach content. Only dichlorvos (2,2 dichlorovinyl O-O dimethylphosphate or DDVP) was found. A simple and rapid method, using DDVP-D₆ as an internal standard, was developed for the determination of DDVP by gas chromatography/mass spectrometry (GC/MS). The method was linear from 1 to 10 mg/L. Intraday and interday precisions were all <15%. DDVP concentration in cardiac blood was approximately four times higher than in peripheral blood. A high concentration was found in the heart showing a cardiac tropism of DDVP, kidney and lung concentrations being much lower. No DDVP was found in liver. DDVP stomach content was 38 g. The amount presumed ingested was 82 g, c . 1000 mg/kg of body. The oral LD₅₀ for DDVP ranges between 20 and 1090 mg/kg in animals but is not known for humans.     

Bupropion Overdose Resulted in a Pharmacobezoar in a Fatal Bupropion (Wellbutrin®) Sustained‐release Overdose: Postmortem Distribution of Bupropion and its Major Metabolites

Bupropion (BUP) overdose commonly causes generalized seizures and central nervous system depression. The case of a 28‐year‐old woman who died from a massive lethal overdose with sustained‐release bupropion (Wellbutrin^® 300 mg) is herein presented. The autopsy revealed the presence of a pharmacobezoar consisting of at least 40 tablets in the stomach. Determination of bupropion and its active metabolites (hydroxybupropion, threobupropion, erythrobupropion) was achieved by a liquid chromatographic mass spectrometry (LC‐MS/MS) method. Postmortem concentrations for bupropion, hydroxybupropion, threobupropion, and erythrobupropion were obtained in intracranial blood, urine, bile, liver, kidney, and vitreous humor. In this case, intracranial blood level of the parent drug was 1.9 mg/L. Threobupropion was the most abundant metabolite in both blood and urine, 59.3 and 890.6 mg/L. Tissue distribution showed the highest concentration in the liver, 12.3 mg/kg. The 0.8 bupropion concentration ratio vitreous/blood suggested that vitreous could be a valuable specimen for toxicological analysis should postmortem blood be unavailable.     

An oxcarbazepine-related fatality with an overview of 26 oxcarbazepine postmortem cases

We present an oxcarbazepine-related fatality together with an overview of 26 postmortem cases involving oxcarbazepine observed during the period 2001-2006. The fatality case concerned a 27-year-old woman with epilepsy, who was found dead in her bed. Oxcarbazepine and its active metabolite, 10-hydroxycarbazepine, were the only compounds detected. The concentrations of oxcarbazepine were as follows: femoral blood, 2.9mg/kg; muscle, 1.8mg/kg; liver, 0.9mg/kg; gastric content (300ml), 860mg/kg; and vitreous humour, not detected. The concentrations of 10-hydroxycarbazepine were as follows: femoral blood, 66mg/kg; muscle, 40mg/kg; liver, 62mg/kg; gastric content, 27mg/kg; and vitreous humour, 25mg/kg. The analyses were performed by HPLC-DAD after liquid-liquid extraction. Oxcarbazepine intoxication was regarded as a possible cause of death. For the other 26 cases, the 10-hydroxycarbazepine concentrations ranged from 2.2 to 48mg/kg with a median of 25mg/kg.     

Tissue distribution of tramadol and metabolites in an overdose fatality

Tramadol (Ultram) is a centrally acting, synthetic analgesic agent. Although it has some affinity for the opiate receptors, tramadol is believed to exert its analgesic effect by inhibiting the re-uptake of norepinephrine and serotonin. There are several published cases of tramadol's involvement in drug-related deaths and impairment. Reports of deaths involving tramadol alone with associated tissue concentrations are rare. This report documents a case in which tramadol overdose was identified as the cause of death. The following tramadol concentrations were found in various tissues: blood, 20 mg/L; urine, 110.2 mg/L; liver, 68.9 mg/kg; and kidney, 37.5 mg/kg. Tissue distributions of the two primary metabolites, N-desmethyl and O-desmethyl tramadol, are also reported. In each tissue or fluid except urine, the tramadol concentration was greater than either metabolite, consistent with other reports of drug-impaired drivers and postmortem cases. The O-desmethyl metabolite concentration was greater than the N-desmethyl metabolite concentration in all tissues; this is in contrast to other postmortem reports, in which the majority of cases report concentrations of O-desmethyl as less than those of N-desmethyl. This may be useful as an indicator of time lapse between ingestion and death.     

An unusual fatality in a child due to oxycodone

An unusual fatality secondary to oxycodone in a child is reported. A 2-year-old female child was conveyed to a local hospital after exhibiting signs of rubbing of the mouth and staggering. A hospital toxicological immunoassay screen for drugs of abuse and tricyclic antidepressants was performed on a urine sample and reported as negative. She was discharged and found unresponsive the next morning. She was conveyed to a second hospital in full cardiopulmonary arrest and despite resuscitative efforts, was pronounced dead upon arrival. An autopsy was performed and postmortem specimens were submitted and screened for drugs using mainly chromatographic techniques. Quantitation was achieved by gas chromatography with nitrogen phosphorus detection. Confirmation was performed by gas chromatography/mass spectrometry. Oxycodone was the only drug detected in the following concentrations: heart blood, 1.36 mg/L; gastric contents, 7.33 mg in 33 mL (222.34 mg/L); liver, 0.2 mg/kg; and urine, 47.23 mg/L (47,230 ng/mL). In addition, immunoassay testing of the urine was positive for the opiate class of drugs. This case report demonstrates an unusual cause of death in a young child with emphasis on potential limitation in hospital urine screening tests and the importance of complete forensic toxicological testing in all child deaths.     

A multi-chemical death involving caffeine, nicotine and malathion

Death of a 21-year-old man who was found in a shower stall in his residence is described in the study. At the scene, a 3/4 filled blue glass bottle labeled "Black Leaf 40" (an insecticide containing nicotine), a white plastic pitcher 1/3 full of thick white fluid, a beer mug 1/4 full of thick white fluid, and an empty carton of milk were found. In addition, a can of malathion and an empty bottle labeled caffeine also were found in the vicinity. Autopsy was performed, and the gross examinations of organs revealed no specific findings to account for the death. However, marked congestion in lung, liver, spleen and kidney were noted at microscopic level. Autolytic degenerative changes were also observed in stomach, small bowel and colon. Toxicological analyses of the autopsy samples (blood, urine, liver and gastric contents) revealed the presence of caffeine and nicotine in each sample. Malathion was found to be present only in gastric content. Caffeine and nicotine were analyzed by utilizing gas liquid chromatography-nitrogen phosphorus detector, while malathion was by gas liquid chromatography-flame photometric detector. Analyses of the fluids from the bottle, pitcher and mug disclosed the presence of nicotine in the concentrations of 17.8%, 3.7% and 5.7% (w/w), respectively. The fluids from the pitcher and mug also contained 2.7-2.9% malathion. Results conclude the death was associated with caffeine, nicotine and malathion.     

A mixed-drug intoxication involving venlafaxine and verapamil

This case report describes the suicide of a 52-year-old woman whose cause of death was attributed to a mixed-drug intoxication involving venlafaxine and verapamil. Venlafaxine is prescribed for the treatment of depression and should be used with caution in patients with cardiovascular disease. Verapamil is a calcium channel blocker primarily used for treatment of cardiovascular disorders. The following drug concentrations were determined in postmortem fluids: verapamil--3.5 mg/L (femoral blood), 9.4 mg/L (subclavian blood), and 1.0 mg/L (vitreous fluid); norverapamil--1.0 mg/L (femoral blood), 2.1 mg/L (subclavian blood), and 0.20 mg/L (vitreous fluid); verapamil and norverapamil could not be detected in bile or urine due to the high levels of erythromycin present; venlafaxine--6.2 mg/L (femoral blood), 8.6 mg/L (subclavian blood), 5.3 mg/L (vitreous fluid), 54.0 mg/L (bile), and 72.3 mg/L (urine); and O-desmethylvenlafaxine--5.4 mg/L (femoral blood), 8.3 mg/L (subclavian blood), positive (vitreous fluid), 29.2 mg/L (bile), and 9.5 mg/L (urine). The cause of death was determined to be a mixed-drug intoxication resulting from an overdose of verapamil and venlafaxine. The manner of death was determined to be suicide.     

Fatal intoxication with labetalol (Trandate)

The dead body of a 44-year-old woman, previously known for depression and alcoholism, has been discovered at her place of residence by her husband. A forensic autopsy has been carried out. The results indicated unspecific histological lesions (alveolar oedema, liver steatosis and interstitial nephritis) but did not reveal any apparent cause of death. Several boxes of medicines have been found near the body, justifying a toxicological analysis. This has been performed on peripheral blood and urine samples using liquid chromatography with diode array and mass spectrometric detections, in conjunction with gas chromatography coupled with mass spectrometry. Ethanol has been found (1.24 g/L in blood, 2.63 g/L in urine and 1.33 g/kg in gastric content), as well as therapeutic concentrations of meprobamate (14.1mg/L) and low concentrations of nordazepam (0.12 mg/L) in blood. On the other hand, particularly high levels of labetalol, a widely used beta-blocker, have been found both in blood (1.7 mg/L) and urine (20.2mg/L), which led us to measure labetalol levels in available viscera samples (liver, heart, kidney, and lung) and gastric content. Measured concentrations were 14.2 microg/g, 7.8 microg/g, 5.4 microg/g, 5.2 microg/g and 31.1 microg/g, respectively. We describe here the first report of a fatal intoxication attributed to labetalol that is linked to its acute toxicity, with tissue distribution of this beta-blocker.     

Fatal intoxication following self-administration of a massive dose of buprenorphine

Several drug packages, including Subutex (high-dose buprenorphine, as sublingual tablets) boxes, were found near the corpse of a 25-year-old male drug addict, who apparently had committed suicide. The autopsy revealed a fatal respiratory depression. The toxicological investigations concluded that death resulted from massive burpienorphine intoxication. The determination of buprenorphine (BU) and norbuprenorphine (NBU) in all biological specimens was performed by liquid chromatography-electrospray mass spectrometry (LC-ES-MS) after hydrolysis (for solid tissues), deproteinization of the matrices, and solid-phase extraction of the compounds. Exceptionally high concentrations of BU and NBU were found in blood (3.3 and 0.4 mg/L, respectively), urine (3.4 and 0.6 mg/L), bile (2035 and 536 mg/L and brain (6.4 a nd 3.9 microg/g). The high concentration of BU (899 mg/L) and the absence of NBU in gastric liquid suggested oral intake. High concentrations of amino-7-flunitra/epam, the main metabolite of flunitra/epam, were also found in blood, urine and gastric liquid. This benzodiazepine may have been a co-factor in the toxic effects of BU.     

Suicidal monointoxication with flunitrazepam. Further comment on coloration phenomena of the upper gastrointestinal tract

Fatal monointoxications with benzodiazepines, for instance with a suicidal intention, are exceptional findings. We report the autopsy case of an 82-year-old woman who died due to a suicidal monointoxication with Rohypnol 1 mg film tablets (therapeutical agent: flunitrazepam). 0.065 mg/L flunitrazepam and 0.34 mg/L 7-aminoflunitrazepam were detected in a postmortem heart blood sample and toxicological analysis revealed the metabolite 7-aminoflunitrazepam in gastric contents, too. At external examination, a bluish-turquoise coloration was seen around the woman's right nostril and within the oral cavity. At autopsy, similar coloration phenomena were seen on the mucosa of the distal esophagus and the stomach. Formerly, bluish stains on mouth and nostrils were considered indicative of intoxications with organophosphates such as parathion (E 605). More recently, case reports accumulate where an intoxication with Rohypnol 1 film tablets (containing the coloring agent indigocarmine in its core) have to be considered as a potential differential diagnosis of such coloration phenomena.     

Tissue distribution of trichloroethylene in a case of accidental acute intoxication by inhalation

This article describes the toxicological findings in a fatality due to an accidental inhalation of trichloroethylene which took place during wall coating of a poorly ventilated well using trichloroethylene. The man was wearing protective clothing and a mouthmask with adsorbent. He was found dead on the floor of the well 5h after descending. Trichloroethylene was added to the mortar to enhance drying. Identification and quantitation of trichloroethylene in the postmortem samples (blood, lung, liver, kidney, stomach content and bile) and identification of its metabolite trichloroacetic acid in urine was performed using static headspace gas chromatography with mass spectrometric detector. The compounds were separated on a CP-SIL 5CB Low Bleed/MS column using n-butanol as internal standard. The method was linear over the specific range investigated, and showed an accuracy of 104% and an intra-day precision of 11%. Trichloroethylene concentrations of 84mg/l in subclavian blood, 40mg/l in femoral blood, 72mg/kg in liver, 12mg/kg in kidney, 78mg/kg in stomach content, 104mg/l in bile and 21mg/kg in lung were found. Trichloroacetic acid was identified in the urine.     

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.     

Comparative studies on tissue distributions of organophosphorus, carbamate and organochlorine pesticides in decedents intoxicated with these chemicals

This paper describes the tissue distributions of dichlorvos, an organophosphate, chlorpyrifos-methyl, an organophosphorothioate, methomyl, a carbamate, and endrin, an organochlorine, in three individuals (Cases 1-3) who died after ingesting insecticidal preparations containing these chemicals. In Case 1 involving dichlorvos and chlorpyrifos-methyl, no dichlorvos was detected in most of the blood and tissue samples. Tiny amounts of dichlorvos (0.067 mg/L and 0.027 mg/L) were detected in the vitreous humor and cerebrospinal fluid, respectively. The chlorpyrifos-methyl concentrations in the blood samples were very site-dependent with a range of 0.615-2.24 mg/L. The tissue concentrations of chlorpyrifos-methyl were within the range 0.379-8.60 mg/kg. The total amounts of dichlorvos and chlorpyrifos-methyl in the stomach were 879 and 612 mg, respectively. The serum cholinesterase activity was 3 IU/L/37 degrees C. In Case 2 involving methomyl, the methomyl concentrations in the blood samples were very site-dependent with a range of 0.56-4.75 mg/L. The tissue concentrations of methomyl were 2.61 mg/kg or less, no methomyl being detected in the spleen, liver and kidney. The methomyl concentrations in the cerebrospinal fluid and vitreous humor were 5.37 and 4.75 mg/L, respectively. The stomach contained 85 mg methomyl. The serum cholinesterase activity was 73 IU/L/37 degrees C. In Case 3 involving endrin, the victim underwent medical treatment for 7 h after ingesting an endrin preparation. The differences in the endrin concentrations among the blood samples were small, with a range of 0.353-0.615 mg/L. The tissue concentrations of endrin were within the range 0.467-13.3 mg/kg. The endrin in the stomach (66 mg) was adsorbed almost completely on the activated charcoal that was administered for medical treatment.     

Concentrations of free-morphine in peripheral blood after recent use of heroin in overdose deaths and in apprehended drivers

The concentration of free-morphine was determined in peripheral (femoral) blood from heroin-related deaths and compared with the concentration in venous blood from impaired drivers. The presence of 6-MAM in blood or urine served as a biomarker for recent use of heroin. Males dominated over females (p<0.001) in both the autopsy cases (88%) and the drivers (91%), although their mean age was about the same 33-35 y (p>0.05). Concentrations of free-morphine in blood were not associated with age of heroin users in Sweden (p>0.05). The median concentration of free-morphine was higher in autopsy cases (0.24 mg/L, N=766) compared with apprehended drivers with 6-MAM in blood (0.15 mg/L, N=124, p<0.05), and appreciably higher than in drivers with 6-MAM in urine but not in blood (0.03 mg/L, N=1823, p<0.001). The free-morphine concentration was above 0.20mg/L in 65% of autopsy cases, 36% of drivers with 6-MAM in blood but only 1.4% of drivers with 6-MAM in urine. Poly-drug deaths had about the same concentrations of free-morphine in blood (0.24 mg/L, N=703) as heroin-only deaths (0.25 mg/L, N=63). The concentration of morphine in drug overdose deaths (median 0.25 mg/L, N=669) was about the same as in traumatic deaths among heroin users (0.23 mg/L, N=97). However, the concentration of morphine was lower when the deceased had consumed alcohol (0.18 mg/L, N=104) compared with taking a benzodiazepine (0.32 mg/L, N=94). The concentration distributions of free-morphine in blood in heroin-related deaths overlapped with the concentrations in impaired drivers, which makes the interpretation of toxicology results difficult without knowledge about tolerance to opiates in any individual case.