Acidic Drug Concentrations in Postmortem Vitreous Humor and Peripheral Blood.

Vitreous humor is a potential alternative matrix for postmortem toxicology drug screens when peripheral blood is unavailable. It is easily and reliably collected and may not suffer from the same postmortem redistribution as seen in blood. Here, we compared the concentrations of 7 acidic drugs (acetaminophen, ibuprofen, naproxen, salicylic acid, carbamazepine, phenobarbital and phenytoin) in peripheral blood and vitreous fluid collected in 89 autopsy cases. Analysis was done by high-performance liquid chromatography with diode-array detection. Overall, we found that vitreous drug concentrations were significantly lower than peripheral blood with median vitreous to peripheral blood (V/PB) ratios ranging from 0.0 to 0.6 (mean, 0.1-0.6). The correlations between the concentrations of over-the-counter analgesics in peripheral blood versus vitreous fluid were poor, with acetaminophen exhibiting the best linearity (R2 = 0.72). The antiepileptic drugs (carbamazepine, phenytoin and phenobarbital) exhibited good correlations between peripheral blood and vitreous humor, with all exhibiting an R2 ≥ 0.95. Overall, we have demonstrated the potential of vitreous fluid as an alternative matrix for the detection of select acidic drugs.

An evaluation of postmortem concentrations of Δ9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH).

Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, leads to impaired cognitive and psychomotor function resulting in an increased risk of fatal motor vehicle collisions and other traumas resulting in death. It is important to measure cannabinoids in postmortem cases to improve understanding of this growing public safety issue. However, postmortem concentrations of THC and its primary inactive metabolite, 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH), have not been extensively studied. We aim to further characterize postmortem concentrations of THC and THCCOOH in peripheral blood with and without preservation, central blood, and central "serum" to support improved forensic interpretation. Cannabinoids were extracted from blood and "serum" from twenty-five decedents using solid phase extraction followed by quantification using gas chromatography - mass spectrometry. We evaluated the impact of sample preservation, reported central blood-to-peripheral blood (CB:PB) ratios and blood-to-"serum" ratios, and assessed the relationship of CB:PB and postmortem interval for THC and THCCOOH. Correlations of preserved compared to unpreserved blood were strong with r2 > 0.97. The median CB:PB ratios were 1.1 and 1.3 for THC and THCCOOH, respectively. THCCOOH CB:PB was significantly higher than 1.0 (p-value < 0.001). The CB:PB ratio was only weakly correlated with PMI for both compounds. The median blood-to-"serum" ratio was 1.0 for THC and 0.8 for THCCOOH. The blood-to-"serum" ratio of THCCOOH was significantly lower than 1.0 (p-value < 0.001). Results demonstrated minimal potential for postmortem redistribution of THC and THCCOOH and that the ratio of blood-to-"serum" in postmortem samples differs from the blood-to-plasma ratio established in living humans. Based on these results, it is not recommended to apply a correction factor to THC and THCCOOH concentrations from postmortem blood samples. Our study improves the understanding of postmortem cannabinoid concentrations to support forensic interpretation in cases of fatal motor vehicle accidents.

A fluvoxamine-related fatality: Case report with postmortem concentrations.

Fluvoxamine is a selective serotonin reuptake inhibitor that has been considered relatively safe in overdose. At therapeutic and supratherapeutic concentrations, fluvoxamine affects cardiac conduction, prolongs QTc interval, causes hypotension, obtundation, and can increase propensity for seizures. A man in his 60s was found dead at his home with a postmortem fluvoxamine peripheral blood concentration of 4.9 mg/L, and a liver concentration of 440 mg/kg. His cause of death was determined to be acute fluvoxamine toxicity.

A Fatality Related to the Synthetic Opioid U-47700: Postmortem Concentration Distribution.

In this case report, we present an evaluation of the distribution of postmortem concentrations of 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) in a fatality attributed principally to the drug. A man who had a history of drug abuse was found unresponsive and not breathing on his bed. Drug paraphernalia, indicating drug insufflation, was located in the decedent's room. Toxicology screening tests in peripheral blood initially identified U-47700 using an alkaline drug screen with gas chromatography-mass spectrometry (GC-MS) following solid-phase extraction. It was subsequently confirmed and quantitated by GC-MS-specific ion monitoring analysis following liquid-liquid extraction. The U-47700 peripheral blood concentration was quantitated at 190 ng/mL compared to the central blood concentration of 340 ng/mL. The liver concentration was 1,700 ng/g, the vitreous was 170 ng/mL, the urine was 360 ng/mL and the gastric contained only a trace amount (<1 mg). Other drugs detected in peripheral blood were alprazolam (0.12 mg/L), nordiazepam (<0.05 mg/L), doxylamine (0.30 mg/L), diphenhydramine (0.14 mg/L), ibuprofen (2.4 mg/L), salicylic acid (<20 mg/L) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (2.4 ng/mL). The cause of death was certified as acute U-47700 and alprazolam abuse, and the manner of death was certified as accident.

A pediatric fatality due to accidental hydromorphone ingestion.

BACKGROUND: Death due to prescription opioid exposure has increased dramatically in North America. Currently, there is a lack of literature detailing potentially lethal doses as well as postmortem tissue analysis concentrations from prescription opioid fatalities in children. We report a pediatric hydromorphone fatality with postmortem peripheral blood, central blood, liver, and gastric concentrations. CASE REPORT: A 3-year-old male was found unresponsive on a couch. Emergency services were contacted and responders found him pulseless, apneic, and asystolic. Resuscitative measures were unsuccessful and he was pronounced dead at a local hospital soon after arrival. Postmortem investigations revealed that two hydromorphone tablets (2 mg each) were missing. There was no demonstrable natural disease or traumatic injury to which to attribute his death upon autopsy; while postmortem concentrations of hydromorphone were confirmed and quantitated in peripheral blood at 0.03 mg/L, central blood 0.06 mg/L, and liver 0.10 mg/kg. CONCLUSION: Given the paucity of reported pediatric opioid-related fatalities, we describe a hydromorphonep-related death in a child, which includes postmortem hydromorphone concentrations.

A tapentadol related fatality: Case report with postmortem concentrations.

Tapentadol (TAP) is an analgesic agent indicated for the management of different types of pain. It has a novel mechanism of action in that it induces analgesia via both µ-opioid receptor agonism and norepinephrine reuptake inhibition. Although deaths associated with TAP use have been reported, there is a paucity of published literature regarding TAP concentrations in biological samples obtained from TAP-associated fatalities. We report a case of TAP toxicity resulting in death with postmortem peripheral and central blood concentrations, liver, vitreous, urine, and gastric contents. A 41-year-old female was found slumped over a sink at home following a welfare check by police. She was transported to a local hospital where she was pronounced dead despite all resuscitative measures. The autopsy was remarkable only for pulmonary edema and signs of aspiration pneumonia. Postmortem concentrations of TAP were confirmed in peripheral blood at 1.1mg/L, central blood 1.3mg/L, liver 9.9mg/kg, vitreous humor 0.94mg/L, urine 88mg/L, and the gastric contained 2mg. Also of note, oxycodone was found in the decedent's blood at a concentration of 0.58mg/L. We report a death related to an intentional ingestion of TAP and oxycodone-the cause and manner of death were determined to be mixed drug intoxication; suicide. We hope that the variety of TAP concentrations identified in this case provide valuable points of reference for future cases of TAP intoxication.

Gabapentin concentrations and postmortem distribution.

Gabapentin is a widely prescribed medication used primarily for the treatment of epilepsy and neuropathic pain. Gabapentin has a favorable adverse effect profile in therapeutic dosing with the most common reported effects being dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional self-poisonings, serious effects are generally rare. In this report, gabapentin analyses were performed on 30 postmortem cases that had peripheral blood, central blood and liver tissue. Overall the central to peripheral blood (C/P) ratio mean was 0.90±0.24 (mean±standard deviation), and a median of 0.97. The liver to peripheral blood (L/P) ratio mean was 0.68±0.26L/kg (mean±standard deviation), and a median of 0.65L/kg. An additional case, where both antemortem blood and postmortem peripheral blood specimens were available, revealed the same gabapentin concentration in both specimens. Taken together, the data presented suggests that gabapentin is unlikely to show postmortem redistribution.

Assessment and Comparison of Vitreous Humor as an Alternative Matrix for Forensic Toxicology Screening by GC-MS.

Alternative specimens have been occasionally considered as substitutes for whole blood for postmortem toxicology testing. We studied the applicability of vitreous humor, and evaluated whether it would be suitable to replace (or augment) whole blood for routine drug screening. Results showed that from 51 autopsy cases, we were able to identify an aggregate of 209 findings in whole blood compared with 169 in vitreous. The total number of compounds identified was 71 for whole blood and 60 for vitreous humor. Quantitative analysis showed that whole-blood concentrations of trazodone were several fold higher than vitreous humor concentrations (1.42 ± 0.57 vs. 0.15 ± 0.05 mg/L, respectively) and similar results were also obtained for diazepam (0.37 ± 0.06 vs. 0.13 ± 0.01, respectively). For other drugs such as oxycodone, hydrocodone and doxylamine, a trend suggesting higher concentrations in vitreous humor vs. whole blood was observed; however, this was not significant. Our results are consistent with the limited work of other investigators, and suggest that vitreous humor could be an appropriate matrix for drug screening in postmortem toxicology.

Synthetic cannabinoid drug use as a cause or contributory cause of death.

Adverse effects associated with synthetic cannabinoid use include agitation, psychosis, seizures and cardiovascular effects, all which may result in a lethal outcome. We report the collection of data from 25 medical examiner and coroner cases where the presence of synthetic cannabinoids was analytically determined. Participating offices provided case history, investigative and relevant autopsy findings and toxicology results along with the cause and manner of death determination. This information, with the agency and cause and manner of death determinations blinded, was sent to participants. Participants offered their opinions regarding the likely contribution of the toxicology findings to cause and manner of death. The results show that some deaths are being attributed to synthetic cannabinoids, with the highest risk areas being behavioral toxicity resulting in excited delirium, trauma or accidents and as contributing factors in subjects with pre-existing cardiopulmonary disease. While insufficient information exists to correlate blood synthetic cannabinoid concentrations to effect, in the absence of other reasonable causes, the drugs should be considered as a cause or contributory cause of death based on history and circumstances with supporting toxicological data.

An Acute Butyr-Fentanyl Fatality: A Case Report with Postmortem Concentrations.

In this case report, we present an evaluation of the distribution of postmortem concentrations of butyr-fentanyl in a fatality attributed principally to the drug. A man who had a history of intravenous drug abuse was found unresponsive on the bathroom floor of his home. Drug paraphernalia was located on the bathroom counter. Toxicology testing, which initially screened positive for fentanyl by enzyme-linked immunosorbent assay, subsequently confirmed butyr-fentanyl, which was then quantitated by gas chromatography-mass spectrometry-specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. The butyr-fentanyl peripheral blood concentration was quantitated at 58 ng/mL compared with the central blood concentration of 97 ng/mL. The liver concentration was 320 ng/g, the vitreous was 40 ng/mL, the urine was 670 ng/mL and the gastric contained 170 mg. Acetyl-fentanyl was also detected in all biological specimens tested. Peripheral blood concentration was quantitated at 38 ng/mL compared with the central blood concentration of 32 ng/mL. The liver concentration was 110 ng/g, the vitreous was 38 ng/mL, the urine was 540 ng/mL and the gastric contained <70 mg. The only other drug detected was a relatively low concentration of benzoylecgonine. The cause of death was certified as acute butyr-fentanyl, acetyl-fentanyl and cocaine intoxication, and the manner of death was certified as accident.

Analytical data supporting the "theoretical" postmortem redistribution factor (Ft ): a new model to evaluate postmortem redistribution.

The concepts of postmortem redistribution (PMR, F) factor, and "theoretical" PMR (Ft ) - based upon a drug's characteristic L/P ratio - have been defined to express the direct relationship between postmortem peripheral blood and the corresponding antemortem whole-blood concentration. This paper applies recent data describing liver/peripheral blood (L/P) ratios for many commonly detected drugs to assess these models, and provide a ranking of drugs' propensity for (and degree of) PMR.

A Fatality Related to Two Novel Hallucinogenic Compounds: 4-Methoxyphencyclidine and 4-Hydroxy-N-methyl-N-ethyltryptamine.

In this case report, we present an evaluation of postmortem concentration distribution of the hallucinogenic compound 4-methoxyphencyclidine (4-MeO-PCP) in a fatality principally attributed to this drug. Another hallucinogen, 4-hydroxy-N-methyl-N-ethyltryptamine was also detected, but was not quantitated. A man--who had a history of recent 'strange' behavior--was found deceased, on his bed, in his locked room. Toxicology testing, which initially screened positive for phencyclidine (PCP) by ELISA, subsequently detected and confirmed the two hallucinogens by gas chromatography-mass spectrometry. 4-MeO-PCP concentrations were then quantified by a specific secondary testing technique. The peripheral blood concentration was 8.2 mg/L compared with the central blood concentration of 14 mg/L. The liver concentration was 120 mg/kg, the vitreous was 5.1 mg/L, the urine was 140 mg/L and the gastric contents contained 280 mg. PCP was not detected, but therapeutic concentrations of venlafaxine, olanzapine, lorazepam and hydroxyzine were confirmed. The cause of death was certified due to acute mixed drug intoxication, and the manner of death was certified as accident.

Comparative analysis of hospital and forensic laboratory ethanol concentrations: A 15 month investigation of antemortem specimens.

Quantitative serum alcohol concentrations from regional hospitals (from specimens collected at time of hospital admission) were compared to results from whole blood (from specimens collected at the time of hospital admission) concentrations measured at the San Diego County Medical Examiner's Office (SDCMEO). Over a 15 month period (January 2012 to March 2013), the postmortem forensic toxicology laboratory analyzed a total of 2,321 cases. Of these, 280 were hospital cases (antemortem) representing 12% of the overall Medical Examiner toxicology casework. 59 of the 280 hospital cases (or 21%) screened positive for alcohol (ethanol). 39 of these 59 cases were included in the study based on available specimens for quantitative analyses. This investigation indicated that serum hospital ethanol concentrations correlated well (R(2) = 0.942) with ethanol values determined at SDCMEO (generally measured in whole blood). There was an observed negative bias with an average of -14.1%. A paired t-test was applied to the data and it was shown that this observed bias is statistically significant. These differences in ethanol concentrations could result from differences in specimen, analytical techniques, and/or calibration. The potential for specimen contamination is also discussed.

Postmortem distribution of trazodone concentrations.

Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to peripheral blood and central blood concentrations in 19 medical examiner cases. Postmortem blood specimens were initially screened for alcohol and simple volatiles, drugs of abuse, and alkaline drugs. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Re-analyses showed that there may be degradation of trazodone in postmortem blood stored at 4°C. There was, on average, about a 20% decrease in samples stored up to eight months. These data suggest that postmortem trazodone peripheral blood concentrations may be considered non-toxic to at least 1.0mg/L with liver concentrations to at least 2.2mg/kg. Overall, trazodone concentrations ranged from 0.08-6.1mg/L in peripheral blood, 0.07-7.1mg/L in central blood, and 0.39-26mg/kg in liver. The median trazodone central blood to peripheral blood ratio was 0.98 (N=19). The liver to peripheral blood ratios showed a median value of 2.8L/kg (N=18). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data demonstrate that trazodone is unlikely to show significant redistribution.

An Acute Acetyl Fentanyl Fatality: A Case Report With Postmortem Concentrations.

In this case report, we present an evaluation of the distribution of postmortem concentrations of acetyl fentanyl in a fatality attributed to the drug. A young man who had a history of heroin abuse was found deceased at his parents' home. Toxicology testing, which initially screened positive for fentanyl by ELISA, subsequently confirmed acetyl fentanyl by gas chromatography-mass spectrometry specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. No other drugs or medications, including fentanyl, were detected. The acetyl fentanyl peripheral blood concentration was quantified at 260 ng/mL compared with the central blood concentration of 250 ng/mL. The liver concentration was 1,000 ng/kg, the vitreous was 240 ng/mL and the urine was 2,600 ng/mL. The cause of death was certified due to acute acetyl fentanyl intoxication, and the manner of death was certified as an accident.

An acute gabapentin fatality: a case report with postmortem concentrations.

Gabapentin (GBP) (Neurontin®, Horizant®, Gralise®) is a widely prescribed medication used primarily for the treatment of epilepsy and neuropathic pain. GBP has a favorable adverse effect profile in therapeutic dosing with the most common reported effects being dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional GBP self-poisonings, serious effects are rare. A 47-year-old female was found dead at work with her daughter's bottle of GBP 600 mg. There were 26 tablets missing and the decedent's only known medication was hydrocodone/acetaminophen. Following initial detection by an alkaline drug screen (GC-MS), analysis utilizing specific liquid chromatography-mass spectrometry revealed an elevated postmortem GBP peripheral blood concentration of 37 mg/L, central blood 32 mg/L, liver 26 mg/kg, vitreous 32 mg/L, and gastric contents 6 mg. Screening for volatiles, drugs of abuse, alkaline compounds, and acid/neutral compounds was negative with the exception of ibuprofen (<2 mg/L) detected in peripheral blood. This report presents a fatality that appears to be associated with an isolated and acute GBP ingestion.

Acute 5-(2-aminopropyl)benzofuran (5-APB) intoxication and fatality: a case report with postmortem concentrations.

A 20-year-old man, a college student, became unresponsive in front of his girlfriend. He was known to consume alcohol and take an unknown drug at some point while in attendance at a local music festival earlier in the day/evening. Upon arrival of emergency personnel, he was noted to be asystolic and apneic. Despite aggressive medical intervention by emergency personnel and at a local hospital emergency room, he was pronounced deceased within 1.25 h of initial medical attention. Postmortem blood initially screened positive for methamphetamine by ELISA. An alkaline drug screen detected 5-(2-aminopropyl)benzofuran (5-APB) which was subsequently confirmed and quantified by a specific GC-MS SIM analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (2.5 mg/L), central blood (2.9 mg/L), liver (16 mg/kg), vitreous (1.3 mg/L), urine (23 mg/L) and gastric contents (6 mg). No other common amphetamine-like compound was detected, although 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB) was presumptively identified in both peripheral blood and urine. Alcohol, the only other drug identified, was confirmed at a concentration of 0.02% (w/v).

Acute 3,4-methylenedioxy-N-ethylcathinone (ethylone) intoxication and related fatality: a case report with postmortem concentrations.

A 30-year-old man reportedly ingested pills and used illicit drugs with another person. They both fell asleep that night and the following afternoon the other person found him dead. There were used hypodermic needles and a metal spoon with dark tarry substance at the death scene, and two recent puncture sites were found on his body. It was uncertain if he had a history of illicit drug use. Postmortem blood initially screened borderline positive for methamphetamine by ELISA. An alkaline drug screen-detected ethylone which was subsequently confirmed and quantified by a specific GC-MS SIM analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (0.39 mg/L), central blood (0.38 mg/L), liver (1.4 mg/kg), vitreous (0.58 mg/L), urine (20 mg/L) and gastric contents (12 mg). Other compounds detected in peripheral blood were morphine (0.05 mg/L), alprazolam (<0.05 mg/L), delta-9-THC (<1 ng/mL), delta-9-carboxy-THC (3.6 ng/mL) and naproxen (<5 mg/L). A urine screen (GC-MS) also confirmed 6-monoacetylmorphine, codeine and sildenafil. The cause of death was certified due to mixed ethylone, heroin and alprazolam intoxication. The manner of death was certified as accident.

Mitragynine 'Kratom' related fatality: a case report with postmortem concentrations.

A 24-year-old man whose medical history was significant for alcohol abuse and depression was found unresponsive in bed. He had several prior suicide attempts with 'pills' and had also been hospitalized for an accidental overdose on a previous occasion. Autopsy findings were unremarkable apart from pulmonary edema and congestion, and urinary retention. Postmortem peripheral blood initially screened positive for mitragynine 'Kratom' (by routine alkaline drug screen by gas chromatography-mass spectrometry, GC-MS), which was subsequently confirmed by a specific GC-MS selective ion mode analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (0.23 mg/L), central blood (0.19 mg/L), liver (0.43 mg/kg), vitreous (<0.05 mg/L), urine (0.37 mg/L) and was not detected in the gastric. Therapeutic concentrations of venlafaxine, diphenhydramine and mirtazapine were also detected together with a negligible ethanol of 0.02% (w/v). The results are discussed in relation to previous cases of toxicity, and the lack of potential for mitragynine postmortem redistribution.