Doxepin and nordoxepin concentrations in body fluids and tissues in doxepin associated deaths

Body fluids and tissues in eight doxepin (Dox)-related deaths were investigated in order to prove whether the individual concentration of Dox, the concentration sum of parent drug and its active metabolite N-desmethyldoxepin (NDox) or the concentration ratio Dox/Ndox valuably contribute to making a cause of death determination. Individual case histories were shortly described. Dox and NDox concentrations were determined by LC–MS/MS. Dox concentration measured from two cases was well within a concentration range considered therapeutic, whereas subtherapeutic dosing may have occurred in another two cases. There were two cases of fatal Dox ingestion, as well as a case of high dosage and advanced putrefaction, respectively. The liver concentration sum may be more useful if a fatal ingestion cannot be clearly separated from a person's medication usage. High concentrations could be observed in lung tissue, and combined concentrations of Dox and NDox may also be helpful in making a cause of death determination. There was a trend to a higher concentration sum in the brain with increasing combined levels in blood. Overall, the sum of the absolute figures allows a more accurate interpretation in Dox-related deaths as compared to the molar concentration ratio which may be helpful in acute ingestion. Determination of the N-desmethyl metabolite along with its parent is recommended and analysis should include more than a single specimen.     

Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance

We reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol (Ultram and Ultracet, Ortho-McNeil) was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Additionally, we reviewed a series of 83 impaired driving cases in which tramadol was detected in order to establish a non-lethal blood tramadol concentration reference range. In both populations, tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. Death was rarely attributable to tramadol alone. However, tramadol may be a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased CNS depression. Although the incidence of tramadol detection has increased consistently over the last eight years, there is no evidence of a corresponding increase in the number of cases in which death was attributed solely to tramadol. Blood drug concentrations in many deaths exceeded the therapeutic serum range of 0.28-0.61 mg/L; however, the concentrations overlapped almost completely with the range identified in living subjects arrested for impaired driving. These findings suggest caution in the interpretation of blood tramadol concentrations outside of the recognized therapeutic range. It also suggests that the drug, even when used in moderate excess, is not a principle cause of death in suicidal or accidental deaths.     

Postmortem oxycodone and hydrocodone blood concentrations

There is limited data on postmortem oxycodone concentrations, consisting of three published reports with a total of 11 cases, many of which were polypharmacy cases. This report presents the results of a review of autopsy and coroner's reports from 10 counties for the years 2000 and 2001 to locate cases with oxycodone or hydrocodone exposure as a leading cause of death. Eighty-eight cases were located. Twenty-four deaths were attributed to oxycodone alone. Mean and median postmortem oxycodone blood concentrations were 1.23 mg/L and 0.43 mg/L, respectively. The range was 0.12 to 8.0 mg/L, with 13 cases (54%) < or = 0.5 mg/L. Seventeen deaths were attributed to hydrocodone alone. Mean and median postmortem hydrocodone blood concentrations were 0.53 mg/L and 0.40 mg/L, respectively. The range was 0.12 to 1.6 mg/L, with 11 cases (65%) < or = 0.5 mg/L. There were seven cases where the cause of death was attributed to the effects of a combination of hydrocodone and oxycodone. Mean oxycodone and hydrocodone blood concentrations were 0.34 mg/L and 0.14 mg/L, respectively. Forty cases involved polysubstance overdoses with significant involvement of other drugs and ethanol. Mean oxycodone and hydrocodone blood concentrations were 0.18 mg/L and 0.29 mg/L, respectively. The list of other substances involved was extensive but included ethanol, amitriptyline, methadone, codeine, propoxyphene, and acetaminophen. The findings of this study report oxycodone values associated with a fatality at blood concentrations lower than previously reported. This may represent enhanced information because of the larger sample group. Hydrocodone values associated with a fatality were similar to previously published values.     

Thiodicarb and methomyl tissue distribution in a fatal multiple compounds poisoning

Abstract:  Thiodicarb is a nonsystemic carbamate insecticide whose acetylcholinesterase activity is related to its main methomyl degradation product. A 40-year-old woman was found dead in her car. Empty packages of medicines and an open bottle of Larvin^® containing thiodicarb were found near her body. No signs of violence nor traumatic injuries were noticed upon autopsy, and police investigations strongly suggested a suicide. Systematic toxicological analysis performed on postmortem specimens revealed the presence of various sedatives, hypnotics, and antipsychotic drugs in blood, urine, and gastric content. Some of the compounds identified were determined at blood concentrations well above the known therapeutic concentrations: zolpidem (2.87 mg/L), bromazepam (2.39 mg/L), nordazepam (4.21 mg/L), and levopremazine (0.64 mg/L). Specific analysis of thiodicarb and of its methomyl metabolite was then performed on all fluids and tissues collected during autopsy by liquid chromatography ion trap tandem mass spectrometry (LC-MS-MS). The anticholinesterase capacity of blood, urine, and gastric content collected at autopsy was 83%, 82%, and 32%, respectively (normal value: 0%). The presence of thiodicarb in the bottle found near the body corroborates the hypothesis of an intake of that compound. Although thiodicarb was only detected in gastric content (24.3 mg/L), its methomyl metabolite was quantified in most postmortem tissues and fluids: gastric content (19.9 mg/L), peripheral blood (0.7 mg/L), urine (8.5 mg/L), bile (2.7 mg/L), liver (0.7 mg/kg), kidney (1.7 mg/kg), lung (1.5 mg/kg), brain (9.3 mg/kg), and heart (3.6 mg/kg).     

Determination of succinyldicholine in different tissue samples from guinea pigs after injection of a single intravenous dose

The distribution and postmortem stability of succinyldicholine in different tissues and urine from guinea-pigs has been studied. Succinyldicholine was extracted from tissue homogenates and urine samples from animals sacrificed by intravenous injections of succinyldicholine hydrochloride (40 mg/kg). The bis-quaternary ammonium compound was demethylated and the tertiary amine was analysed by gas chromatography/mass spectrometry. The concentrations found in muscle, kidney and urine were often low; in muscle below 5 pmol/g, in kidney from 5 to 1500 pmol/g and in urine from 5 to 650 pmol/ml. The eye proved to be the best tissue sample, with a rather high and constant concentration (280 +/- 36 pmol/g) of succinyldicholine. The postmortem stability was studied by storing the bodies at 4 degrees C. After 6 days storage the drug concentrations in the eyes started to decline. Four weeks after death it was not possible to detect any succinyldicholine in this tissue.     

Determination of morphine in postmortem rabbit bone marrow and comparison with blood morphine concentrations

The aim of this study is to predict how long after time of death a buried body could be analyzed for opiates in soft tissues and to show the accessibility and suitability of bone marrow as a useful toxicological specimen from buried bodies. Morphine solutions were injected in nine albino rabbits. Doses ranged from 0.3 to 1.1 mg/kg with 0.1 mg/kg increments. One hour after the injections, the rabbits were sacrificed. Blood, urine and bone marrow samples were collected for analysis. After the whole bodies were buried, femur bone marrow specimens were collected on the seventh and fourteenth days. CEDIA was used to monitor morphine contents of the collected samples. All experimental cases showed that the increase in the given morphine doses correlated with the increase in blood and bone marrow morphine concentrations. High morphine concentrations were detected in urine samples, but there was no correlation between the urine and blood or urine and bone marrow morphine concentrations. Statistically meaningful increases in bone marrow morphine concentrations were found parallel to increase of blood morphine concentrations. Seventh and fourteenth day postmortem morphine concentrations also followed this correlation. Morphine concentrations in bone marrow at 7 and 14 day postmortem decreased consistently when compared with bone marrow morphine concentrations collected immediately after death. We conclude that in sudden death when other specimens are unavailable due to degradation, bone marrow can be a most useful specimen. Further experimental research in this area is required to validate bone marrow as an alternative tissue.     

阿维菌素在急性中毒死家兔体内的再分布研究

目的考察阿维菌素在急性中毒死家兔体内的再分布。方法按最小致死量一次性灌胃250mg/kg阿维菌素,HPLC法检测家兔死后0h、24h、48h和72h中阿维菌素的含量。结果给家兔一次性灌胃250mg/kg阿维菌素的临床死亡时间为120.6±9.2min(±s,n=10);测定了阿维菌素的致死血浓度和致死组织浓度;家兔死后0h~72h心血和各主要脏器组织中阿维菌素含量存在体内再分布现象;确定肝、肾、肺为最佳组织检材。结论阿维菌素在急性中毒死家兔体内的再分布数据,对法医办理此类案件具有重要参考价值。     

Fatal dextropropoxyphene poisonings in Jutland, Denmark

For many years dextropropoxyphene (dxp) has been the medicament most frequently occurring in drug poisoning cases examined at the Institute of Forensic Medicine, University of Aarhus. This study includes 85 cases of acute fatal poisoning examined in the period 1985-1987 in which dxp alone (40 cases) or in combination with alcohol (29 cases) and/or other drugs (16 cases) contributed significantly to death. Two-thirds of the deceased were men and one-third women. The average age was 37 years for both sexes. More than half of the deceased were drug and/or alcohol misusers. Eighteen were drug addicts. Half of the deaths resulted from accidents, while 40% were suicides. Accidental deaths prevailed among younger men. In a majority of the cases the drug had been taken orally. In these cases the median total blood concentration of dxp and the metabolite nordextropropoxyphene (ndxp) was 17 mg/kg in the suicide cases and 7.1 mg/kg in the accident cases. The corresponding figures for dxp without metabolite were 9.4 mg/kg and 2.2 mg/kg, respectively. The median value of the quotient dxp/ndxp was 1.9 in the suicide cases and 0.5 in the accident cases. The quotient, together with the concentrations of the drug, may therefore indicate the manner of death in many cases.     

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.     

Postmortem atropine concentrations in resuscitation cases

The medications used during resuscitation are often in and of themselves toxic. Several reports have been published regarding toxicities of these drugs, including lidocaine, procainamide, and atropine. But how does a forensic pathologist or toxicologist differentiate a possible intoxication from therapeutic or resuscitory use especially given that the concentrations of such drugs, when used in the setting of resuscitation, have not been studied? Concentrations of a well-known resuscitation medication, atropine, were assessed in cases where it was administered before death during attempted resuscitation in an effort to address this deficiency. A review of deaths occurring in 2009 was undertaken to identify cases where drugs known to be used during resuscitation were present on toxicological analysis. Autopsy reports and medical records were examined to determine how much atropine was administered, the timing and route of administration, the time the sample was drawn (antemortem and postmortem), the source of the sample, and the ultimate cause of death. Eighty-nine cases were identified in which atropine was given before death during attempted resuscitation and was detected in the blood on postmortem toxicological screening; 11 cases were identified in which atropine was administered before death yet was not detected on the postmortem toxicological screening. Mean age was 41 years, and there were 65 males and 35 females. The overall median dose of atropine given was 3 mg, the median difference between the time of last administration of the atropine to the time of death (or draw for antemortem samples) was 15 minutes, and the median atropine concentration was 0.1 mg/L. Analysis failed to reveal significant differences in the atropine concentration based on the route of administration (intravenous or intraosseus), the cause of death, or the time since administration (within the first 2 hours). Analysis did reveal a difference between the atropine concentrations in peripheral versus central blood sources and with prolonged postmortem interval (>24 hours) suggesting postmortem redistribution.     

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.     

Postmortem investigation of lamotrigine concentrations

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.     

Postmortem Fluid Concentrations of Heroin Biomarkers and Their Metabolites

Only limited data exist concerning the utility of complementary specimens in heroin-related deaths. As such, this report employed a validated LC-MS-MS method to quantify 6-monoacetylmorphine (6-MAM), 6-acetylcodeine (6-AC), and their metabolites morphine and codeine in blood with (BN) and without preservative (B) and the additional unpreserved specimens of vitreous humor, urine, stomach contents, and bile from 20 postmortem cases in which heroin was the primary cause of death. The median concentration of 6-MAM in BN was 0.011 mg/L, B was 0.008 mg/L, urine was 0.186 mg/L, vitreous humor was 0.022 mg/L, stomach contents was 0.147 mg/L, and bile was 0.012 mg/L. Only one case was found to be positive for 6-AC in B (case 6, 0.002 mg/L), and the median concentration of 6-AC was 0.002 mg/L in BN, 0.012 mg/L in urine, 0.003 mg/L in vitreous humor, 0.057 mg/L in stomach contents, and 0.004 mg/L in bile. These findings present new information on the distribution of these analytes in complementary matrices and support their inclusion for accurately determining the role of heroin in opioid-related deaths.     

“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.     

Postmortem urine immunoassay showing false-positive phencyclidine reactivity in a case of fatal tramadol overdose

This is a report of postmortem false-positive reactivity using an enzyme-multiplied urine phencyclidine (PCP) immunoassay (EMIT II+) due to a single-agent fatal tramadol overdose. An autopsy of a 42-year-old male who died alone at home revealed no identifiable lethal anatomic abnormalities, thus leading to toxicologic analysis. Femoral blood was obtained for drug testing by high-performance liquid chromatography (HPLC) and showed a tramadol level of 14.0 mg/L, 2 orders of magnitude greater than the therapeutic range (0.1 to 0.3 mg/L). Urine was also obtained and EMIT II+ immunoassay revealed positivity for PCP at 88 mAU/min. However, confirmatory testing by HPLC failed to identify PCP in either the urine or serum. To verify the suspicion that this was a false-positive PCP result, stock solutions of tramadol and its major metabolite (O-desmethyltramadol) at concentrations of 100 mg/L in 10% methanol/H2O were compared with a blank solution (10% methanol/H2O) for EMIT II+ PCP reactivity and demonstrated reactivities of 44 mAU/min and 27 mAU/min, respectively. While these individual results were below the cutoff reactivity for a positive EMIT II+ PCP result (ca. 85 mAU/min), they were much more reactive than the blank calibrator (set at 0 mAU/min). Therefore, we conclude that the immunoreactivity of tramadol and its metabolites in aggregate is responsible for the PCP immunoassay interference and false-positive result.     

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.     

Fatal unintentional intoxications with tramadol during 1995-2005

Tramadol is an extensively used centrally acting analgesic and is considered a safe drug devoid of many serious adverse effects of traditional opioids. However, recently, toxicity and an abuse potential of tramadol have been reported. This study examined fatal unintentional tramadol intoxications among Swedish forensic autopsy cases between 1995 and 2005. All fatal intoxications were selected, in which toxic concentrations of tramadol (>1 microg/g femoral blood) had been detected, and where the forensic pathologist considered the intoxication unintentional and the fatal outcome at least partly explained by tramadol. Toxicology analyses, police reports, autopsy protocols and medical records were scrutinized. A total of 17 cases (eleven men and six women) of fatal unintentional tramadol intoxications were identified. For these cases the median age was 44 years (range 18-78 years) and the median tramadol concentration was 2.0 microg/g (range 1.1-12.0 microg/g). Other pharmaceutical substances, illicit drugs or ethanol were detected in addition to tramadol in all of these cases. In fact, intoxication with multiple drugs was considered the cause of death in 10 (59%) cases. However, in seven cases tramadol was the only substance present in toxic concentrations. A history of substance abuse was identified in 14 (82%) subjects and a present tramadol abuse in 8 (47%). These results suggest that fatal intoxications with tramadol may occur unintentionally and that subjects with a history of substance abuse may be at certain risk. Precaution is therefore warranted when prescribing tramadol in such patients.     

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.     

Postmortem hydroxychloroquine concentrations in nontoxic cases

Hydroxychloroquine (HCQ) is a 4-aminoquinoline compound used to treat malaria and chronic autoimmune disorders and is not uncommonly found in the medical examiner setting. Studies have shown HCQ to have a long half-life (32-56 days in blood), high volume of distribution (580-815 L/kg), and therapeutic concentrations ranging from 0.03 to 15 mg/L, depending on the chronicity of treatment. Previous reports have shown that the toxic concentration of HCQ ranges from 3 to 26 mg/L, whereas the lethal concentration ranges from 20 to 104 mg/L. A report addressing nontoxic postmortem concentrations of HCQ in individuals known to be taking the medication, and in whom there is no evidence of toxicity, has not been previously undertaken. This study found that postmortem concentrations in nontoxic cases can range from 0.3 to 39 mg/L, which is well within the reported range of both lethal and toxic concentrations. It is recommended that all investigative and autopsy data be considered and that the cause of death not be certified based purely on blood HCQ concentrations.